Blog

  • Chemo/Radiation Did Not Yield Increased Pelvic Malignancies in Rectal Cancer

    Chemo/Radiation Did Not Yield Increased Pelvic Malignancies in Rectal Cancer

    In patients with rectal cancer, the median OS was 12 years in the chemotherapy and radiation therapy group vs 24 years in the chemotherapy alone group.

    Concurrent chemotherapy with radiation therapy did not significantly increase the cumulative incidence of second pelvic malignancies, though it did increase the cumulative incidence of second non-pelvic malignancies compared with chemotherapy alone in patients with locally advanced rectal cancer, according to results from a study shared in the International Journal of Radiation Oncology, Biology, Physics.

    In the concurrent chemotherapy group, the 5- and 10-year cumulative incidences of second pelvic malignancy development was 2.1% (95% CI, 1.4%-3.0%) and 5.8% (95% CI, 4.2%-7.6%); in the chemotherapy alone group, the rates were 2.3% (95% CI, 0.92%-4.8%) and 4.2% (95% CI, 1.3%-9.8%), respectively. This difference did not reach statistical significance (Gray’s Test P = .3).

    A multivariable analysis showed that older age was associated with second pelvic malignancies (MV HR, 3.03; 95% CI, 1.39-6.60; P = .005), though chemotherapy alone was not significantly associated with fewer second pelvic malignancies (MV HR, 0.66; 95% CI, 0.30-1.44; P = .3).

    Intensity-modulated radiation therapy and volumetric modulated arc therapy techniques were associated with reduced risk of second pelvic malignancies vs conventional and 3D conformal radiation therapy on univariable analysis (P = .014).

    The most common second pelvic malignancies were prostate adenocarcinoma (31%; n = 23) and uterine cancer (28%; n = 21); uterine cancers were mostly serous, clear cell, or endometrioid, though 5 patients in the concurrent chemotherapy group developed carcinosarcomas.

    The 10-year cumulative incidence of non-pelvic second malignancies was 11.0% (95% CI, 9.1%-14.1%) in the concurrent chemotherapy group and 4.4% (95% CI, 2.2%-7.9%) in the chemotherapy alone group (Gray’s Test P = .017).

    Univariable analysis showed that being older than 50 was significantly associated with increased risk of second non-pelvic malignancies (HR, 2.48; 95% CI, 1.40-4.11; P ≤.001), and being male was associated with a decreased risk (HR, 0.61; 95% CI, 0.44-0.85; P = .004). Further, diabetes was associated with a second non-pelvic cancer (HR, 1.51; 95% CI, 1.05-2.19; P = .028), and abstaining from tobacco decreased the risk of second non-pelvic cancer (HR, 0.63; 95% CI, 0.43-0.91; P = .013).

    The most common second non-pelvic cancers were lung cancer (24%; n = 35), breast cancer (15%; n = 21), and hematologic malignancies (13%; n = 19). While 77% of those who developed a second non-pelvic cancer did not have a diagnosis of any other cancer, 13% did also develop a second pelvic malignancy.

    Regarding radiation dosimetry and technique, 21 patients who developed a second pelvic malignancy had a chemotherapy plan available; of the 21, 9 developed uterine cancer with a mean dose of 4800cGy (range, 4296-5087).

    The median overall survival (OS) in the concurrent chemotherapy group was 12 years (95% CI, 11-13) vs 24 years (95% CI, 15-unreached) in the chemotherapy alone cohort. The 5- and 10-year OS rates for those who received concurrent chemotherapy for rectal cancer was 78% (95% CI, 76%-80%) and 58% (95% CI, 55%-61%), respectively; in those who received chemotherapy alone, the rates were 88% (95% CI, 84%-91%) and 76% (95% CI, 70%-82%).

    The 10-year survival for those who did not develop second pelvic malignancies was 60% (95% CI, 57%-63%) vs 77% (95% CI, 67%-87%) in those who did develop a second pelvic malignancy (P = .042).

    “These data serve as a foundation for future prospective studies evaluating ways to further reduce the risk of second malignancies in high-risk patients undergoing [concurrent chemotherapy] for rectal cancer,” wrote lead study author Carla Hajj, MD, of the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center, and coauthors, in the paper. “Areas of potential investigation include personalized treatments using more modern technologies such as proton beam [radiation therapy] or MRI-based treatment deliveries, lifestyle changes, and robust survivorship programs.”

    The study included 2624 patients with locally advanced rectal cancer, of whom 460 were treated with chemotherapy without radiation therapy and 2164 received concurrent chemotherapy. The most common adjuvant chemotherapy regimens were folinic acid, fluorouracil (5FU), and oxaliplatin (FOLFOX; 60%), 5FU (32%), and capecitabine/oxaliplatin (CapeOx; 4%).

    Eligible patients had disease treated with chemotherapy with or without pelvic radiation therapy who were identified from an institutional database by Cancer Database, ICD-9/10, and ICD-0 histologic diagnosis codes for “rectum” or “rectosigmoid”.

    Patients were ineligible for participation if they had received prior pelvic radiation therapy or if their treatment was for recurrent disease.

    Second malignancies were defined as those preceding the rectal cancer diagnosis date by more than 6 months, synchronous cancers were defined as within 6 months of diagnosis, and metachronous cancers were defined as occurring between 6 months and 2 years after diagnosis. A second cancer was defined as occurring more than 2 years after diagnosis of locally advanced rectal cancer. The development of a non-pelvic cancer did not preclude capturing the diagnosis of a second pelvic cancer.

    Reference

    Tringale KR, Patel KH, Hilal L, et al. Development of second malignancies following chemotherapy with or without radiation therapy for the treatment of locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. Published online July 19, 2025. doi:10.1016/j.ijrobp.2025.07.1424

    Continue Reading

  • Türkiye confirm title intentions with win over Serbia

    Türkiye confirm title intentions with win over Serbia

    The official EuroBasket app

    RIGA (Latvia) – There was drama, there was tension, and there was a level of basketball which is simply hard to describe by just using words.

    Türkiye and Serbia battled in the last game of the Group Phase in Group A, both entering the matchup with perfect 4-0 records.

    After 8 ties and 15 lead changes, Türkiye remained on top, collecting a 95-90 win and securing a Round of 16 matchup with Sweden on Saturday.

    Meanwhile, Serbia will play against Finland on the same day, in the same phase of competition.

    Turning Point

    Sehmus Hazer’s three-pointer gave Türkiye an 89-88 lead with just under two minutes to play.

    Nikola Jokic responded with a tip-in, clearing up Nikola Jovic’s miss under the rim, but Alperen Sengun drove straight at him and drew a foul to give Türkiye another lead with 41.5 to play.

    He then decided it was time to win the game on the defensive end, stealing the ball out of Marko Guduric’s hands and allowing Shane Larkin to ice the game from the free throw line with 15.5 left on the game clock.

    When Jokic missed the three-pointer on the other end, Sengun picked up the rebound and sealed the deal.

    TCL Player of the Game

    Alperen Sengun heard the MVP chants from the small but loud group of Turkish fans among the 6,113 in Arena Riga, and presented with the challenge called Nikola Jokic, he absolutely deserved hearing it.

    The big guy was all over the place, drawing “oohs” and “ahhs” from the crowd with each drive, pass or shot, and in the end, celebrated not just winning the matchup, winning the game, but also winning the group.

    He finished with 28 points, 13 rebounds and 8 assists on the day, claiming another TCL Player of the Game award.

    Stats Don’t Lie

    Türkiye shot the ball exceptionally well, knocking down 15-of-25 three-pointers through three quarters, and finishing the game shooting 18-of-31 from range.

    While Serbia weren’t that far off in the shooting department, defeating Ergin Ataman’s men on such a hot shooting day is almost impossible.

    Bottom Line

    We already said Türkiye are going to need support from the other guys, but their Big Three combo of Sengun, Cedi Osman and Shane Larkin is still one of the strongest to ever appear in FIBA EuroBasket games, combining for 67 points on the day.

    For the first time since 2009, they have won five straight FIBA EuroBasket games.

    Meanwhile, Serbia got 22 points, 9 rebounds and 4 assists from Nikola Jokic, but they suffered their first group stage defeat since 2017.

    They won the points in the paint 42-26, showing that their strength is still under both rims.

    They Said

    For quotes, tune in to the official post-game press conference!

    FIBA

    Continue Reading

  • Cannabis Products Show Long-Term Sleep Benefits

    Cannabis Products Show Long-Term Sleep Benefits

    Cannabis may offer lasting sleep and anxiety relief for people battling chronic insomnia. Credit: SciTechDaily.com

    A long-term study suggests that cannabis-based medical treatments may bring lasting relief to people with chronic insomnia.

    Over 18 months, patients reported not only better sleep but also reduced anxiety, less depression, and even lower pain levels. Side effects were mild and temporary for most, making cannabis a potential alternative where traditional sleep medications fall short.

    Cannabis-Based Products Show Promise

    People living with insomnia who used cannabis-based medical treatments reported sleeping better for as long as 18 months, according to research published August 27 in the open-access journal PLOS Mental Health. The study was led by Arushika Aggarwal of Imperial College London, U.K., along with her colleagues.

    Sleep problems affect roughly one in three people, and about 10 percent of adults meet the criteria for an insomnia disorder. Standard treatment options are often hard to access, and medications approved for insomnia carry a risk of dependence.

    To explore whether cannabis-based therapies might ease insomnia, the researchers reviewed outcomes from 124 patients who were prescribed medical cannabis. They tracked changes in reported sleep quality, anxiety and depression levels, and overall quality of life across one to 18 months of treatment.

    Lasting Sleep and Mental Health Benefits

    Patients consistently reported better sleep throughout the 18-month period. They also noted reduced anxiety and depression, along with lower levels of pain. Around nine percent experienced side effects such as fatigue, dry mouth, or insomnia, but none were considered serious. While more rigorous randomized controlled trials are required to confirm safety and effectiveness, the results suggest that cannabis-based medical products may provide a new avenue for improving sleep among people with chronic insomnia.

    Co-author Dr. Simon Erridge, Research Director at Curaleaf Clinic, explained: “Over an 18-month period, our study showed that treatment for insomnia with cannabis-based medicinal products was associated with sustained improvements in subjective sleep quality and anxiety symptoms. These findings support the potential role of medical cannabis as a medical option where conventional treatments have proven ineffective, though further randomised trials are needed to confirm long-term efficacy.”

    Importance of Long-Term Monitoring

    He adds: “Conducting this long-term study provided valuable real-world evidence on patient outcomes that go beyond what we typically see in short-term trials. It was particularly interesting to observe signs of potential tolerance over time, which highlights the importance of continued monitoring and individualised treatment plans.”

    Reference: “UK Medical Cannabis Registry: A clinical outcomes analysis for insomnia” by Arushika Aggarwal, Simon Erridge, Isaac Cowley, Lilia Evans, Madhur Varadpande, Evonne Clarke, Katy McLachlan, Ross Coomber, James J. Rucker, Mark W. Weatherall and Mikael H. Sodergren, 27 August 2025, PLOS Mental Health.
    DOI: 10.1371/journal.pmen.0000390

    Never miss a breakthrough: Join the SciTechDaily newsletter.

    Continue Reading

  • RNA CAR T Shows Promise for Myasthenia Gravis

    RNA CAR T Shows Promise for Myasthenia Gravis

    Development of B-cell maturation antigen (BCMA)–directed RNA chimeric antigen receptor T-cell therapy (rCAR T) to treat refractory generalized myasthenia gravis (MG) should continue, write experts in a recent issue of Annals of Clinical & Translational Neurology.1 Their investigation of patients who received Descartes-08, a BCMA-directed autologous rCAR T, in 6 weekly infusions demonstrated disease severity improvement as soon as 3 months after initial administration, with 72% of the treated patients maintaining their treatment response at 12 months.

    “Unlike conventional CAR-T cell therapies that rely on in vivo T-cell expansion to achieve therapeutic concentration, Descartes-08 undergoes ex vivo T-cell proliferation during manufacturing, enabling controlled dosing,” the study authors wrote. “This process allows Descartes-08 to be administered in the outpatient setting and does not require lymphodepleting chemotherapy.”

    The treatment dosage of Descartes-08 was 52.5 x 106 cells/kg administered on days 1, 8, 15, 22, 29, and 36.

    The phase 1/2a study that provided the data for this analysis took place at community and academic medical centers. Seven patients were included, 5 of whom were female patients. Three of these patients were acetylcholine receptor antibody–positive (AChR Ab+), 2 were muscle-specific tyrosine kinase antibody positive (MuSK Ab+), and 1 was seronegative (had no antibodies for AChR, MuSK, or low-density lipoprotein receptor–related protein 4). For patient outcomes at 2, 3, 6, 9, and 12 months, improvement was evaluated using 4 scales: MG Activities of Daily Living (MG-ADL), MG Composite (MGC), Quantitative MG (QMG), and MG quality of life 15-revised score (QOL-15r).

    At baseline, 5 of the 7 patients continued to receive a median dose of 17.5 mg/d of prednisone; this decreased by 5 mg/day by month 12. No patients required intravenous immunoglobulin over the year of follow-up. Between months 3 and 6 after the final infusion, results fluctuated for MG-ADL between 6-point and 8-point improvements in disease severity; for MGC, between 15-point and 20-point improvements; and for QOL-15, between 10-point and 15-point improvements. Steady improvement was seen per QMG, with an 8-point improvement seen at 3 months, which increased to an approximate 12-point improvement. For MG-ADL, MGC, and QMG, a clinically meaningful decrease was at least a 2-point improvement.

    In this investigation, there were no overall reports of anaphylaxis or hematologic toxicity, and total immunoglobulin levels did not significantly decrease. | Image Credit: © ArtemisDiana-stock.adobe.com

    By month 9, the authors were seeing that all their patients were experiencing ongoing improvement, per mean changes in the following:

    • MG-ADL: −6.3 (95% CI, −3.5 to −9.1)
    • MGC: −16.6 (95% CI, −13.4 to −19.5)
    • QMG: −8.4 (95% CI, −5.2 to −11.6)
    • QoL-15r: −12.0 (95% CI, −8.0 to −16.0)

    These results were maintained for 5 of the 7 patients at the 12-month follow-up:

    • MG-ADL: −4.6 (95% CI, −8.8 to −0.4)
    • MGC: −11.3 (95% CI, −18.0 to −4.6)
    • QMG −6.3 (95% CI, −10.5 to −2.0)
    • QoL-15r: −7.7 (95% CI, −15.6 to −8.4)

    Patients could be retreated if they met prespecified criteria, and of the 3 participants who relapsed or did not maintain treatment response, all experienced improvement with retreatment. The retreatment dose was once again 52.5 x 106 cells/kg, administered once weekly for 6 weeks.

    Anti-meningococcal antibodies from prior vaccination were seen at baseline in 5 of 7 patients, and following a modest decrease in these at month 3 that deepened by month 9, month 12 brought stabilization. These patients also reported fewer adverse events.

    Prior research on Descartes-08 demonstrated similar deep and durable responses,2 the present study authors noted, adding strength to their new findings; in particular, that retreatment results were similar to or better than initial treatment. There also were no overall reports of anaphylaxis or hematologic toxicity, and total immunoglobulin levels did not significantly decrease.

    “The use of mRNA for autologous CAR T-cell engineering may decrease the risk of several toxicities commonly associated with CAR-Ts engineered with integrating vectors,” the investigators stated. “The favorable safety profile of Descartes-08 contrasts with DNA-based CAR-Ts, which carry oncogenic risk from genomic integration of CAR DNA and require lymphodepletion chemotherapy with potential hematologic toxicities.”

    Still, there are limitations on these findings, with the authors noting research needs to continue to answer 3 questions in particular: how durable are responses in the absence of ongoing treatment? Is retreatment achievable in any/all instances of disease worsening? What is the long-term impact of BCMA-directed mRNA CAR T on immunoglobulin levels and vaccine titers?

    References

    1. Chahin N, Sahagian G, Feinberg MH, et al. Durability of response to B-cell maturation antigen-directed mRNA cell therapy in myasthenia gravis. Ann Clin Transl Neurol. Published online August 26, 2025. doi:10.1002/acn3.70167
    2. Granit V, Benatar M, Kurtoglu M, et al; MG-001 study team. Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study. Lancet Neurol. 2023;22(7):578-590. doi:10.1016/S1474-4422(23)00194-1

    Continue Reading

  • The Butterfly Star And Its Planet-Forming Disk

    The Butterfly Star And Its Planet-Forming Disk

    The Taurus star-forming region is only a few hundred light-years away, and it may be the nearest star formation region to Earth. It’s a stellar nursery with hundreds of young stars, and attracts a lot of astronomers’ attention. One of the young stars in Taurus is named IRAS 04302. IRAS 04302 is sometimes called the “Butterfly Star” because of its appearance when viewed edge-on.

    The JWST image of IRAS 04302 is the latest ESA/Webb Picture of the Month.

    Astronomers are intensely interested in the details of planet formation, and one of the JWST’s science goals is the study of planets forming in protoplanetary disks around young stars like IRAS 04302. Many of the images we have of planets forming in protoplanetary disks come from ALMA, the Atacama Large Millimeter/submillimeter Array. These images show the disks in a “top down” orientation. In those images, astronomers can spot the rings and gaps that signal planet formation.

    ALMA has captured many images of protoplanetary disks around young stars. These three are typical, and show gaps and rings where planets are likely forming. As young planets take shape, they sweep up gas and dust in the disk, creating the gaps. Image Credit: ALMA/ESO

    IRAS 04302 is oriented so that we see its protoplanetary disk from the side. IRAS 04302 is a fine example of a young star that is still accreting mass while planets could be forming in its protoplanetary disk, and the edge-on view provides more than just a pretty picture. This viewpoint gives astronomers a different look at disks. It shows the disk’s vertical structure and can reveal how thick the dusty disk is.

    In this image, the dust disk acts almost like a coronagraph, blocking out some of the star’s light and making detail in the disk stand out. Reflection nebulae on either side of the disk are illuminated by the star, giving IRAS 04302 its nickname Butterfly Star.

    The image is created from the JWST’s Mid-Infrared Instrument (MIRI) and Near-Infrared Camera (NIRCam), and the Hubble also contributed optical data. The Webb shows how dust grains are distributed and how dust extending out from the disk reflects near-infrared light. The Hubble shows the dust lane itself, as well as clumps and streaks, evidence that the star is still gathering mass. It also shows jets and outflows, more evidence of its ongoing growth.

    IRAS 04302 as imaged with the JWST. The disk is about 65 million km across, making it several times larger than our Solar System. Image Credit: ESA/Webb, NASA & CSA, M. Villenave et al. LICENCE: CC BY 4.0 INT IRAS 04302 as imaged with the JWST. The disk is about 65 million km across, making it several times larger than our Solar System. Image Credit: ESA/Webb, NASA & CSA, M. Villenave et al. LICENCE: CC BY 4.0 INT

    There’s no scientific journal devoted solely to protoplanetary disk, but there could be, considering how much research goes into them. These JWST images are more than just pictures, they’re associated with a study published in The Astrophysical Journal titled “JWST Imaging of Edge-on Protoplanetary Disks. II. Appearance of Edge-on Disks with a Tilted Inner Region: Case Study of IRAS04302+2247.” The lead author is Marion Villenave from NASA’s Jet Propulsion Laboratory.

    “Because planet formation occurs in the protoplanetary disk phase, studying protoplanetary disk evolution can allow us to better understand planet formation,” the article’s authors write. The main thrust of this type of research is to understand how tiny dust particles gradually form kilometer-sized bodies that eventually form planetesimals and then planets. It can take only a few million years, or even less, for these kilometer-size rocks to form. One of the big questions is sometimes called the “Bouncing Barrier.” The problem is that once dust grains reach a certain size, their collisions are more energetic. Instead of sticking to one another, they bounce off each other. For planetesimals to form, some force has to overcome the Bouncing Barrier.

    This figure from the research is an image gallery of the JWST observations of IRAS04302. Image Credit: M. Villenave et al. 2025. ApJ This figure from the research is an image gallery of the JWST observations of IRAS04302. Image Credit: M. Villenave et al. 2025. ApJ

    “In the current paradigm, high dust concentrations are thought to accelerate grain growth by promoting disk instabilities that lead to planetesimal formation (e.g., streaming instability), and subsequently allowing efficient growth via pebble accretion,” the authors write.

    Answers to the Bouncing Barrier and other questions regarding planet formation can only be found in protoplanetary disks. In this research, the scientists examined IRAS 04302’s edge-on disk hoping to find clues. One of the answers to planet formation questions may lie in dust settling.

    “Dust vertical settling in the disk is the result of gas drag on dust grains subject to stellar gravity and gas turbulence,” the authors write. “This mechanism leads large dust grains to fall into the disk midplane and accumulate there, which is favorable for planet formation.” The authors note that this mechanism is poorly constrained by observations.

    This is why IRAS 04302 is such a desirable target.

    “Highly inclined protoplanetary disks are favorable targets to investigate this mechanism because they allow a direct view of the disk’s vertical structure,” the researchers explain.

    The authors observed that IRAS 04302’s inner disk is tilted and asymmetrical, as are 15 out of 20 other observed edge-on disks. If tilt and asymmetry are this common, it has implications. It affects how disks evolve and how their dynamics play out. In turn, it must affect how planets form, and what the eventual architecture of a solar system will be.

    This figure shows 20 observed edge-on disks. 15 of them show clear asymmetry, while five do not. Though the five that are considered symmetrical have some curves, they're not curved enough to be considered asymmetrical. Image Credit: M. Villenave et al. 2025. ApJ This figure shows 20 observed edge-on disks. 15 of them show clear asymmetry, while five do not. Though the five that are considered symmetrical have some curves, they’re not curved enough to be considered asymmetrical. Image Credit: M. Villenave et al. 2025. ApJ

    The researchers didn’t reach a clear conclusion for how all of this works. No single study can answer all of our questions, but each one nudges us toward a greater understanding. They note that further observations will deepen their understanding of tilted disks and how they affect planet formation.

    Continue Reading

  • Nanoprobe achieves sharper MRIs of the inner ear

    Nanoprobe achieves sharper MRIs of the inner ear

     

    Doctors often struggle to get clear images of the inner ear, a tightly protected organ encased in bone. The body’s natural obstacles make it difficult to get magnetic resonance imaging (MRI) contrasts into the ear to diagnose tumors, infections, or malformations. Now a team of researchers has developed a nanoparticle-based MRI contrast that can grab on to inner ear cells and sneak its way inside (Chem. Biomed. Imaging 2025, DOI: 10.1021/cbmi.5c00049).

    “Standard . . . imaging agents rarely reach this tissue and clear out very fast, forcing clinicians to use higher doses, which raises the risk of hearing damage and toxicity,” says Huan Wang, a biomedical chemist at Changchun Institute of Applied Chemistry and the study’s senior author. The challenge comes from a protective set of cells lining the blood vessels between the middle and inner labyrinth of the ear—the blood-labyrinth barrier, or BLB.

    This cellular defense allows nutrients and oxygen to pass through but blocks other molecules, including many drugs and contrast agents. To address this, Wang’s team has created the first guided MRI nanoprobe shown to cross this BLB and accumulate in the inner ear.

    The probe combines three features: an iron oxide core just 3.3 nm across that serves as the MRI contrast, a polyethylene glycol (PEG) coating that keeps the contrast circulating in the bloodstream, and a short peptide intermingled with the PEG called IETP2.

    Wang explains that the IETP2 sticks to LRP1—a receptor found throughout the body but especially abundant in the BLB—which is able to ferry useful molecules across the barrier, essentially letting the nanoprobe hitch a ride into the inner ear. “By attaching the nanoparticles to a peptide which targets the receptor on the BLB, the team found a way to push the probes past the barrier,” says Carmen Burtea, a biomedical imaging researcher at Université de Mons who was not involved in the study.

    In mice, the nanoprobes crossed the BLB efficiently and stayed in circulation long enough to reach the cochlea. They produced up to 84% stronger MRI signals than untargeted controls, with no damage to any major organs.

    “The untargeted version of the nanoprobe is already known to enhance contrast at lower doses than [standard] gadolinium agents,” Burtea says. She adds that if the probe passes risk assessments, it could give doctors a new tool to diagnose both fluid buildup and structural changes within the inner ear.

    Wang agrees that clinical translation will require toxicology tests and larger-animal studies. Johannes Gerb, a biomedical imaging researcher at Ludwig Maximilian University Munich who also was not involved in the study, notes that if the probe can match gadolinium’s performance at lower cost and with comparable safety in humans, “it could become a viable alternative.”

    Looking ahead, Wang says that “the platform can also be used as a general platform to ferry drugs or gene therapies to the inner ear,” though he cautions that avoiding unintended delivery to other LRP1-expressing tissues would require troubleshooting. The potential also resonates with clinicians. “Modalities such as this are an exciting avenue as they can definitely reduce the toxic loads of current medications,” says Rajesh Bhardwaj, an otolaryngologist at MedFirst ENT Centre in India who was not involved in the study.

    Chemical & Engineering News

    ISSN 0009-2347

    Copyright ©
    2025 American Chemical Society

    Continue Reading

  • Dollar falls versus yen and Swiss franc following US jobs data – Reuters

    1. Dollar falls versus yen and Swiss franc following US jobs data  Reuters
    2. U.S. Dollar Pulls Back As JOLTs Job Openings Drop: Analysis For EUR/USD, GBP/USD, USD/CAD, USD/JPY  FXEmpire
    3. USD: The really big chunks are yet to come – Commerzbank  FXStreet
    4. Currency markets are looking forward to a pivotal week as the dollar awaits employment data  المتداول العربي
    5. Dollar weak as cracks in US labour market spur rate cut bets  Reuters

    Continue Reading

  • Guide to ‘Waiting for Godot’ on Broadway starring Keanu Reeves and Alex Winter

    Guide to ‘Waiting for Godot’ on Broadway starring Keanu Reeves and Alex Winter

    Cue up another excellent adventure. Keanu Reeves and Alex Winter, two individually renowned screen actors jointly famous for their Bill & Ted films, are now taking the stage in a new production of Waiting for Godot on Broadway, one that marks Reeves’s Broadway debut and Winter’s return after 40-plus years.

    The longtime real-life pals lead Samuel Beckett’s absurdist classic about two hapless vagabonds endlessly anticipating a no-show’s arrival. Tony Award nominee Jamie Lloyd (Sunset Boulevard), a director who makes the most of minimalist stagings, steers the starry revival at the Hudson Theatre.

    Learn more about the play and its storied history with the FAQs below, and don’t wait to secure your seats on New York Theatre Guide.

    Get Waiting for Godot tickets now.

    Continue Reading

  • Targeting MHC-E as a new strategy for vaccines and immunotherapeutics

    Targeting MHC-E as a new strategy for vaccines and immunotherapeutics

  • Trowsdale, J. & Knight, J. C. Major histocompatibility complex genomics and human disease. Annu. Rev. Genom. Hum. Genet. 14, 301–323 (2013).

    Article 
    CAS 

    Google Scholar 

  • D’Souza, M. P. et al. Casting a wider net: immunosurveillance by nonclassical MHC molecules. PLoS Pathog. 15, e1007567 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Braud, V. M. et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795–799 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Borrego, F., Ulbrecht, M., Weiss, E. H., Coligan, J. E. & Brooks, A. G. Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J. Exp. Med. 187, 813–818 (1998).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lee, N. et al. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc. Natl Acad. Sci. USA 95, 5199–5204 (1998). This seminal study, together with Braud et al. (1998) and Borrego et al. (1998), identifies the role of HLA-E binding to CD94–NKG2A and CD94–NKG2C in modulating NK cell activation according to levels of HLA-Ia signal sequence presentation on the target cell.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Aldrich, C. J. et al. Identification of a Tap-dependent leader peptide recognized by alloreactive T cells specific for a class Ib antigen. Cell 79, 649–658 (1994).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lee, N., Goodlett, D. R., Ishitani, A., Marquardt, H. & Geraghty, D. E. HLA-E surface expression depends on binding of TAP-dependent peptides derived from certain HLA class I signal sequences. J. Immunol. 160, 4951–4960 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Braud, V., Jones, E. Y. & McMichael, A. The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9. Eur. J. Immunol. 27, 1164–1169 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Knapp, L. A., Cadavid, L. F. & Watkins, D. I. The MHC-E locus is the most well conserved of all known primate class I histocompatibility genes. J. Immunol. 160, 189–196 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Geraghty, D. E., Stockschleader, M., Ishitani, A. & Hansen, J. A. Polymorphism at the HLA-E locus predates most HLA-A and -B polymorphism. Hum. Immunol. 33, 174–184 (1992).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Strong, R. K. et al. HLA-E allelic variants. Correlating differential expression, peptide affinities, crystal structures, and thermal stabilities. J. Biol. Chem. 278, 5082–5090 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Gillespie, G. M., Quastel, M. N. & McMichael, A. J. HLA-E: immune receptor functional mechanisms revealed by structural studies. Immunol. Rev. 329, e13434 (2025). This work provides a comprehensive review of structural and biochemical studies of HLA-E.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • van Hall, T., Oliveira, C. C., Joosten, S. A. & Ottenhoff, T. H. The other Janus face of Qa-1 and HLA-E: diverse peptide repertoires in times of stress. Microbes Infect. 12, 910–918 (2010).

    Article 
    PubMed 

    Google Scholar 

  • Wei, X. H. & Orr, H. T. Differential expression of HLA-E, HLA-F, and HLA-G transcripts in human tissue. Hum. Immunol. 29, 131–142 (1990).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Middelburg, J. et al. The MHC-E peptide ligands for checkpoint CD94/NKG2A are governed by inflammatory signals, whereas LILRB1/2 receptors are peptide indifferent. Cell Rep. 42, 113516 (2023). This paper shows that MHC-E is a ligand for inhibitory receptors LIR1 and LIR2 irrespective of peptide ligand. Using CRISPR screening, the authors also identify gene products involved in processing of VL9 peptides.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Braud, V. M., Allan, D. S., Wilson, D. & McMichael, A. J. TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide. Curr. Biol. 8, 1–10 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • He, W. et al. Intracellular trafficking of HLA-E and its regulation. J. Exp. Med. 220, e20221941 (2023). This study shows that the cytoplasmic tail of HLA-E contains internalization signals, which explains the short half-life of HLA-E on the cell surface.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Phillips, J. H. et al. CD94 and a novel associated protein (94AP) form a NK cell receptor involved in the recognition of HLA-A, HLA-B, and HLA-C allotypes. Immunity 5, 163–172 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Le Drean, E. et al. Inhibition of antigen-induced T cell response and antibody-induced NK cell cytotoxicity by NKG2A: association of NKG2A with SHP-1 and SHP-2 protein-tyrosine phosphatases. Eur. J. Immunol. 28, 264–276 (1998).

    Article 
    PubMed 

    Google Scholar 

  • Carretero, M. et al. Specific engagement of the CD94/NKG2-A killer inhibitory receptor by the HLA-E class Ib molecule induces SHP-1 phosphatase recruitment to tyrosine-phosphorylated NKG2-A: evidence for receptor function in heterologous transfectants. Eur. J. Immunol. 28, 1280–1291 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lanier, L. L., Corliss, B., Wu, J. & Phillips, J. H. Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity 8, 693–701 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Horowitz, A. et al. Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry. Sci. Transl. Med. 5, 208ra145 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mingari, M. C. et al. HLA class I-specific inhibitory receptors in human T lymphocytes: interleukin 15-induced expression of CD94/NKG2A in superantigen- or alloantigen-activated CD8+ T cells. Proc. Natl Acad. Sci. USA 95, 1172–1177 (1998).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Andre, P. et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell 175, 1731–1743.e13 (2018). This study shows that HLA-E–NKG2A is a new immune checkpoint for cancer therapy because blocking NKG2A increases the anti-tumour activity of NK cells and of tumour-specific T cells, including those induced by cancer vaccines.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kaiser, B. K., Pizarro, J. C., Kerns, J. & Strong, R. K. Structural basis for NKG2A/CD94 recognition of HLA-E. Proc. Natl Acad. Sci. USA 105, 6696–6701 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kaiser, B. K. et al. Interactions between NKG2x immunoreceptors and HLA-E ligands display overlapping affinities and thermodynamics. J. Immunol. 174, 2878–2884 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • MacLachlan, B. J., Sullivan, L. C., Brooks, A. G., Rossjohn, J. & Vivian, J. P. Structure of the murine CD94-NKG2A receptor in complex with Qa-1b presenting an MHC-I leader peptide. FEBS J. 291, 1530–1544 (2024). This paper shows that the high-resolution structure of CD94–NKG2A with the murine MHC-E homologue Qa-1b shows similarities and differences compared with their human counterparts, thus paving the way for a humanized mouse.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Michaëlsson, J. et al. A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition. J. Exp. Med. 196, 1403–1414 (2002).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Huisman, B. D. et al. High-throughput characterization of HLA-E-presented CD94/NKG2x ligands reveals peptides which modulate NK cell activation. Nat. Commun. 14, 4809 (2023). This work has developed a systematic screen of peptides binding to HLA-E and their effect on receptor binding that reveals differential peptide specificities of CD94–NKG2A and CD94–NKG2C.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Willcox, B. E., Thomas, L. M. & Bjorkman, P. J. Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor. Nat. Immunol. 4, 913–919 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Shiroishi, M. et al. Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proc. Natl Acad. Sci. USA 100, 8856–8861 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Horowitz, A. et al. Class I HLA haplotypes form two schools that educate NK cells in different ways. Sci. Immunol. 1, eaag1672 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lin, Z. et al. HLA class I signal peptide polymorphism determines the level of CD94/NKG2-HLA-E-mediated regulation of effector cell responses. Nat. Immunol. 24, 1087–1097 (2023). This work shows that VL9 sequence polymorphism in HLA alleles is reflected in HCMV UL40 VL9 and impacts NK cell responses.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cazzetta, V., Depierreux, D., Colucci, F., Mikulak, J. & Mavilio, D. NKG2A immune checkpoint in Vδ2 T cells: emerging application in cancer immunotherapy. Cancers 15, 1264 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rapaport, A. S. et al. The inhibitory receptor NKG2A sustains virus-specific CD8+ T cells in response to a lethal poxvirus infection. Immunity 43, 1112–1124 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, X., Feng, J., Chen, S., Yang, H. & Dong, Z. Synergized regulation of NK cell education by NKG2A and specific Ly49 family members. Nat. Commun. 10, 5010 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kaulfuss, M. et al. The NK cell checkpoint NKG2A maintains expansion capacity of human NK cells. Sci. Rep. 13, 10555 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Siemaszko, J., Marzec-Przyszlak, A. & Bogunia-Kubik, K. Activating NKG2C receptor: functional characteristics and current strategies in clinical applications. Arch. Immunol. Ther. Exp. 71, 9 (2023).

    Article 
    CAS 

    Google Scholar 

  • Lauterbach, N., Wieten, L., Popeijus, H. E., Voorter, C. E. & Tilanus, M. G. HLA-E regulates NKG2C+ natural killer cell function through presentation of a restricted peptide repertoire. Hum. Immunol. 76, 578–586 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Rolle, A., Meyer, M., Calderazzo, S., Jager, D. & Momburg, F. Distinct HLA-E peptide complexes modify antibody-driven effector functions of adaptive NK cells. Cell Rep. 24, 1967–1976.e4 (2018). This study shows that the HLA-E ligandome affects the activity and proliferation of NKG2C+ NK cells.

    Article 
    PubMed 

    Google Scholar 

  • Lopez-Verges, S. et al. Expansion of a unique CD57+NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc. Natl Acad. Sci. USA 108, 14725–14732 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Foley, B. et al. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood 119, 2665–2674 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lopez-Botet, M., De Maria, A., Muntasell, A., Della Chiesa, M. & Vilches, C. Adaptive NK cell response to human cytomegalovirus: facts and open issues. Semin. Immunol. 65, 101706 (2023). This paper provides a comprehensive review of HCMV-induced adaptive NK cells.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Della Chiesa, M. et al. Human cytomegalovirus infection promotes rapid maturation of NK cells expressing activating killer Ig-like receptor in patients transplanted with NKG2C−/− umbilical cord blood. J. Immunol. 192, 1471–1479 (2014).

    Article 
    PubMed 

    Google Scholar 

  • Luetke-Eversloh, M. et al. Human cytomegalovirus drives epigenetic imprinting of the IFNG locus in NKG2Chi natural killer cells. PLoS Pathog. 10, e1004441 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lee, J. et al. Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals. Immunity 42, 431–442 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Schlums, H. et al. Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42, 443–456 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Gao, F. et al. Biology and clinical relevance of HCMV-associated adaptive NK cells. Front. Immunol. 13, 830396 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Costa-Garcia, M. et al. Antibody-mediated response of NKG2Cbright NK cells against human cytomegalovirus. J. Immunol. 194, 2715–2724 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ulbrecht, M. et al. Cutting edge: the human cytomegalovirus UL40 gene product contains a ligand for HLA-E and prevents NK cell-mediated lysis. J. Immunol. 164, 5019–5022 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Tomasec, P. et al. Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287, 1031 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Powers, C. J. & Früh, K. Signal peptide-dependent inhibition of MHC class I heavy chain translation by rhesus cytomegalovirus. PLoS Pathog. 4, e1000150 (2008).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Brackenridge, S. et al. Regulation of the cell surface expression of classical and non-classical MHC proteins by the human cytomegalovirus UL40 and rhesus cytomegalovirus Rh67 proteins. J. Virol. 98, e0120624 (2024). This study shows that UL40 and Rh67 of HCMV and RhCMV, respectively, not only promote MHC-E egress to the cell surface via their VL9 sequences but also retain classical MHC-I proteins in the ER.

    Article 
    PubMed 

    Google Scholar 

  • Hammer, Q. et al. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat. Immunol. 19, 453–463 (2018). This paper shows that VL9 sequences determine NKG2C-dependent NK cell activation.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Koldehoff, M., Ross, S. R., Dührsen, U., Beelen, D. W. & Elmaagacli, A. H. Early CMV-replication after allogeneic stem cell transplantation is associated with a reduced relapse risk in lymphoma. Leuk. Lymphoma 58, 822–833 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ram, D. R. et al. Tracking KLRC2 (NKG2C)+ memory-like NK cells in SIV+ and rhCMV+ rhesus macaques. PLoS Pathog. 14, e1007104 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Truitt, L. L. et al. Impact of CMV infection on natural killer cell clonal repertoire in CMV-naive rhesus macaques. Front. Immunol. 10, 2381 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Martin Almazan, N. et al. Non-classical HLA-E restricted CMV 15-mer peptides are recognized by adaptive NK cells and induce memory responses. Front. Immunol. 14, 1230718 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wilkinson, G. W. et al. Modulation of natural killer cells by human cytomegalovirus. J. Clin. Virol. 41, 206–212 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Redondo-Pachon, D. et al. Adaptive NKG2C+ NK cell response and the risk of cytomegalovirus infection in kidney transplant recipients. J. Immunol. 198, 94–101 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ataya, M. et al. Long-term evolution of the adaptive NKG2C+ NK cell response to cytomegalovirus infection in kidney transplantation: an insight on the diversity of host-pathogen interaction. J. Immunol. 207, 1882–1890 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Vietzen, H. et al. Extent of cytomegalovirus replication in the human host depends on variations of the HLA-E/UL40 axis. mBio 12, e02996–02920 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Vietzen, H., Pollak, K., Honsig, C., Jaksch, P. & Puchhammer-Stockl, E. NKG2C deletion is a risk factor for human cytomegalovirus viremia and disease after lung transplantation. J. Infect. Dis. 217, 802–806 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Mittelbronn, M. et al. Elevated HLA-E levels in human glioblastomas but not in grade I to III astrocytomas correlate with infiltrating CD8+ cells. J. Neuroimmunol. 189, 50–58 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Gooden, M. et al. HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8+ T lymphocytes. Proc. Natl Acad. Sci. USA 108, 10656–10661 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Benevolo, M. et al. High expression of HLA-E in colorectal carcinoma is associated with a favorable prognosis. J. Transl. Med. 9, 184 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Seliger, B. et al. HLA-E expression and its clinical relevance in human renal cell carcinoma. Oncotarget 7, 67360–67372 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kamiya, T., Seow, S. V., Wong, D., Robinson, M. & Campana, D. Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells. J. Clin. Invest. 129, 2094–2106 (2019). This paper implicates NKG2A as a checkpoint for NK cell-mediated killing of tumour cells; see also Andre et al. (2018) and van Montfoort et al. (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Iyer, R. F. et al. CD8+ T cell targeting of tumor antigens presented by HLA-E. Sci. Adv. 10, eadm7515 (2024). This work shows that RhCMV vectors expressing tumour-associated antigens elicit strong MHC-E-restricted T cell responses in non-human primates that cross-react with HLA-E-expressing human cancer cells.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wen, M. et al. Expression and clinical significance of NKG2A and HLA-E in advanced laryngeal carcinoma. Pathol. Res. Pract. 260, 155383 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Liu, X. et al. Immune checkpoints HLA-E:CD94-NKG2A and HLA-C:KIR2DL1 complementarily shield circulating tumor cells from NK-mediated immune surveillance. Cell Discov. 10, 16 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, X. et al. Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance. Cancer Cell 41, 272–287.e9 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • van Hall, T. et al. Monalizumab: inhibiting the novel immune checkpoint NKG2A. J. Immunother. Cancer 7, 263 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lin, A. & Yan, W. H. Heterogeneity of HLA-G expression in cancers: facing the challenges. Front. Immunol. 9, 2164 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Liu, W. et al. FcRγ gene editing reprograms conventional NK cells to display key features of adaptive human NK cells. iScience 23, 101709 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lo Monaco, E. et al. Human leukocyte antigen E contributes to protect tumor cells from lysis by natural killer cells. Neoplasia 13, 822–830 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Green, M. L. et al. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood 122, 1316–1324 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Elmaagacli, A. H. et al. Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. Blood 118, 1402–1412 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Cichocki, F. et al. Adaptive NK cell reconstitution is associated with better clinical outcomes. JCI Insight 4, e125553 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Litjens, N. H. R., van der Wagen, L., Kuball, J. & Kwekkeboom, J. Potential beneficial effects of cytomegalovirus infection after transplantation. Front. Immunol. 9, 389 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Chiu, E. et al. Anti-NKG2C/IL-15/anti-CD33 killer engager directs primary and iPSC-derived NKG2C+ NK cells to target myeloid leukemia. Mol. Ther. 29, 3410–3421 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Cho, H. et al. Adaptive natural killer cells facilitate effector functions of daratumumab in multiple myeloma. Clin. Cancer Res. 27, 2947–2958 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Bigley, A. B. et al. Latent cytomegalovirus infection enhances anti-tumour cytotoxicity through accumulation of NKG2C+ NK cells in healthy humans. Clin. Exp. Immunol. 185, 239–251 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Murad, S. et al. NKG2C+ NK cells for immunotherapy of glioblastoma multiforme. Int. J. Mol. Sci. 23, 5857 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Haroun-Izquierdo, A. et al. Adaptive single-KIR+NKG2C+ NK cells expanded from select superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia. J. Immunother. Cancer 10, e005577 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • van Montfoort, N. et al. NKG2A blockade potentiates CD8 T cell immunity induced by cancer vaccines. Cell 175, 1744–1755.e15 (2018). Using mouse models of cancer, this study shows that cancer vaccines elicit NKG2A-expressing T cells that are less effective at controlling cancers unless NKG2A is blocked.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sheffer, M. et al. Genome-scale screens identify factors regulating tumor cell responses to natural killer cells. Nat. Genet. 53, 1196–1206 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Li, Y. et al. Unlocking the therapeutic potential of the NKG2A-HLA-E immune checkpoint pathway in T cells and NK cells for cancer immunotherapy. J. Immunother. Cancer 12, e009934 (2024). This work is a recent review of ongoing clinical studies of NKG2A-targeting and HLA-E-targeting immune checkpoint inhibitors.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fisher, J. G., Graham, L. V. & Blunt, M. D. Strategies to disrupt NKG2A:HLA-E interactions for improved anti-cancer immunity. Oncotarget 15, 501–503 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Borst, L. et al. NKG2A is a late immune checkpoint on CD8 T cells and marks repeated stimulation and cell division. Int. J. Cancer 150, 688–704 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Abd Hamid, M. et al. Enriched HLA-E and CD94/NKG2A interaction limits antitumor CD8+ tumor-infiltrating T lymphocyte responses. Cancer Immunol. Res. 7, 1293–1306 (2019).

    Article 
    PubMed 

    Google Scholar 

  • Chen, Y. et al. CD8+ T cells form the predominant subset of NKG2A+ cells in human lung cancer. Front. Immunol. 10, 3002 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Fesneau, O. et al. IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cells. Nat. Commun. 15, 9988 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Speiser, D. E. et al. In vivo expression of natural killer cell inhibitory receptors by human melanoma-specific cytolytic T lymphocytes. J. Exp. Med. 190, 775–782 (1999).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ducoin, K. et al. Targeting NKG2A to boost anti-tumor CD8 T-cell responses in human colorectal cancer. Oncoimmunology 11, 2046931 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Salomé, B. et al. NKG2A and HLA-E define an alternative immune checkpoint axis in bladder cancer. Cancer Cell 40, 1027–1043.e9 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Battin, C. et al. NKG2A-checkpoint inhibition and its blockade critically depends on peptides presented by its ligand HLA-E. Immunology 166, 507–521 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Eugene, J. et al. The inhibitory receptor CD94/NKG2A on CD8+ tumor-infiltrating lymphocytes in colorectal cancer: a promising new druggable immune checkpoint in the context of HLAE/β2m overexpression. Mod. Pathol. 33, 468–482 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Haanen, J. B. & Cerundolo, V. NKG2A, a new kid on the immune checkpoint block. Cell 175, 1720–1722 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Aggarwal, C. et al. Updated results from COAST, a phase 2 study of durvalumab (D) ± oleclumab (O) or monalizumab (M) in patients (pts) with stage III unresectable non-small cell lung cancer (uNSCLC). J. Clin. Oncol. 42, 8046 (2024).

    Article 

    Google Scholar 

  • Barlesi, F. et al. PACIFIC-9: phase III trial of durvalumab + oleclumab or monalizumab in unresectable stage III non-small-cell lung cancer. Future Oncol. 20, 2137–2147 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Spinosa, P. et al. Quantitative modeling predicts competitive advantages of a next generation anti-NKG2A monoclonal antibody over monalizumab for the treatment of cancer. CPT Pharmacomet. Syst. Pharmacol. 10, 220–229 (2021).

    Article 
    CAS 

    Google Scholar 

  • Zhou, Y. et al. Generation, characterization, and preclinical studies of a novel NKG2A-targeted antibody BRY805 for cancer immunotherapy. Antibodies 13, 93 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ravindranath, M. H., Filippone, E. J., Devarajan, A. & Asgharzadeh, S. Enhancing natural killer and CD8+ T cell-mediated anticancer cytotoxicity and proliferation of CD8+ T cells with HLA-E monospecific monoclonal antibodies. Monoclon. Antib. Immunodiagn. Immunother. 38, 38–59 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hwang, J. K. et al. HLA-E-VL9 antibodies enhance NK cell and CD8+ T cell cytotoxicity against HIV-infected CD4+ T cells. Preprint at bioRxiv https://doi.org/10.1101/2024.07.08.602401 (2024).

  • Carlsten, M. et al. Bortezomib sensitizes multiple myeloma to NK cells via ER-stress-induced suppression of HLA-E and upregulation of DR5. Oncoimmunology 8, e1534664 (2019).

    Article 
    PubMed 

    Google Scholar 

  • Tsao, H.-W. et al. Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint. Immunity 57, 2863–2878 (2024). This study shows the utility of targeting ERAP (which is known to be required for VL9 processing for presentation by HLA-E) as a strategy for inhibiting HLA-E–NKG2A-mediated checkpoint control of NK cell and CD8+ T cell activity.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Fisher, J. G. et al. XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression. Leukemia 37, 2036–2049 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Westin, J. R. et al. Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed/refractory aggressive B-cell lymphomas: observations from the JULIET, ZUMA-1, and TRANSCEND trials. Am. J. Hematol. 96, 1295–1312 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hong, M. & Chen, Y. Y. Killer fatigue: transition to NK-cell-like phenotype is a signature of CAR-T cell exhaustion. Cell 184, 6017–6019 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Good, C. R. et al. An NK-like CAR T cell transition in CAR T cell dysfunction. Cell 184, 6081–6100.e26 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Myers, J. A. & Miller, J. S. Exploring the NK cell platform for cancer immunotherapy. Nat. Rev. Clin. Oncol. 18, 85–100 (2021).

    Article 
    PubMed 

    Google Scholar 

  • Bexte, T. et al. CRISPR/Cas9 editing of NKG2A improves the efficacy of primary CD33-directed chimeric antigen receptor natural killer cells. Nat. Commun. 15, 8439 (2024). This paper shows that CAR NK cell activity against CD33-expressing target cells can be improved by gene editing to remove NKG2A expression.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Saetersmoen, M. et al. Targeting HLA-E-overexpressing cancers with a NKG2A/C switch receptor. Med 6, 100521 (2024). This paper shows that a fusion protein design of the NKG2A ligand-binding domain with the NKG2C signalling domain combines the increased affinity of NKG2A for VL9–HLA-E with the activating signalling provided by NKG2C.

    Article 
    PubMed 

    Google Scholar 

  • Voogd, L. et al. Mtb-specific HLA-E-restricted T cells are induced during Mtb infection but not after BCG administration in non-human primates and humans. Vaccines 12, 1129 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Mazzarino, P. et al. Identification of effector-memory CMV-specific T lymphocytes that kill CMV-infected target cells in an HLA-E-restricted fashion. Eur. J. Immunol. 35, 3240–3247 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Garcia, P. et al. Human T cell receptor-mediated recognition of HLA-E. Eur. J. Immunol. 32, 936–944 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Pietra, G. et al. HLA-E-restricted recognition of cytomegalovirus-derived peptides by human CD8+ cytolytic T lymphocytes. Proc. Natl Acad. Sci. USA 100, 10896–10901 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Romagnani, C. et al. HLA-E-restricted recognition of human cytomegalovirus by a subset of cytolytic T lymphocytes. Hum. Immunol. 65, 437–445 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Jouand, N. et al. HCMV triggers frequent and persistent UL40-specific unconventional HLA-E-restricted CD8 T-cell responses with potential autologous and allogeneic peptide recognition. PLoS Pathog. 14, e1007041 (2018). This study shows that UL40-encoded VL9 sequences can be targeted by HLA-E-restricted T cells in HCMV-infected humans.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Rousseliere, A., Delbos, L., Bressollette, C., Berthaume, M. & Charreau, B. Mapping and characterization of HCMV-specific unconventional HLA-E-restricted CD8 T cell populations and associated NK and T cell responses using HLA/peptide tetramers and spectral flow cytometry. Int. J. Mol. Sci. 23, 263 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Allard, M. et al. HLA-E-restricted cross-recognition of allogeneic endothelial cells by CMV-associated CD8 T cells: a potential risk factor following transplantation. PLoS ONE 7, e50951 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sullivan, L. C. et al. The presence of HLA-E-restricted, CMV-specific CD8+ T cells in the blood of lung transplant recipients correlates with chronic allograft rejection. PLoS ONE 10, e0135972 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Waters, S. et al. Do variations in the HLA-E ligand encoded by UL40 distinguish individuals susceptible to HCMV disease? Hum. Immunol. 84, 75–79 (2022).

    Article 
    PubMed 

    Google Scholar 

  • Tarrago, D., Gonzalez, I. & Gonzalez-Escribano, M. F. HLA-E restricted cytomegalovirus UL40 peptide polymorphism may represent a risk factor following congenital infection. BMC Genom. 23, 455 (2022).

    Article 
    CAS 

    Google Scholar 

  • Sullivan, L. C. et al. Natural killer cell receptors regulate responses of HLA-E-restricted T cells. Sci. Immunol. 6, eabe9057 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Sullivan, L. C. et al. A conserved energetic footprint underpins recognition of human leukocyte antigen-E by two distinct αβ T cell receptors. J. Biol. Chem. 292, 21149–21158 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hoare, H. L. et al. Structural basis for a major histocompatibility complex class Ib-restricted T cell response. Nat. Immunol. 7, 256–264 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Lo Monaco, E. et al. HLA-E: strong association with β2-microglobulin and surface expression in the absence of HLA class I signal sequence-derived peptides. J. Immunol. 181, 5442–5450 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Brackenridge, S., John, N., Früh, K., Borrow, P. & McMichael, A. J. The antibodies 3D12 and 4D12 recognise distinct epitopes and conformations of HLA-E. Front. Immunol. 15, 1329032 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Walters, L. C. et al. Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding. Nat. Commun. 9, 3137 (2018). This paper shows that HLA-E can bind a wide variety of peptides, and it suggests that some of the peptides targeted by CD8+ T cells bind very poorly to HLA-E.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Grant, E. J. et al. The unconventional role of HLA-E: the road less traveled. Mol. Immunol. 120, 101–112 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Pietra, G., Romagnani, C., Manzini, C., Moretta, L. & Mingari, M. C. The emerging role of HLA-E-restricted CD8+ T lymphocytes in the adaptive immune response to pathogens and tumors. J. Biomed. Biotechnol. 2010, 907092 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lampen, M. H. et al. Alternative peptide repertoire of HLA-E reveals a binding motif that is strikingly similar to HLA-A2. Mol. Immunol. 53, 126–131 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • McMurtrey, C. et al. T cell recognition of Mycobacterium tuberculosis peptides presented by HLA-E derived from infected human cells. PLoS ONE 12, e0188288 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ruibal, P. et al. Peptide binding to HLA-E molecules in humans, nonhuman primates, and mice reveals unique binding peptides but remarkably conserved anchor residues. J. Immunol. 205, 2861–2872 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Celik, A. A., Kraemer, T., Huyton, T., Blasczyk, R. & Bade-Doding, C. The diversity of the HLA-E-restricted peptide repertoire explains the immunological impact of the Arg107Gly mismatch. Immunogenetics 68, 29–41 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Kraemer, T. et al. HLA-E: presentation of a broader peptide repertoire impacts the cellular immune response-implications on HSCT outcome. Stem Cell Int. 2015, 346714 (2015).

    Google Scholar 

  • Weitzen, M., Shahbazy, M., Kapoor, S. & Caron, E. Deciphering the HLA-E immunopeptidome with mass spectrometry: an opportunity for universal mRNA vaccines and T-cell-directed immunotherapies. Front. Immunol. 15, 1442783 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • van Hall, T. et al. The varicellovirus-encoded TAP inhibitor UL49.5 regulates the presentation of CTL epitopes by Qa-1b1. J. Immunol. 178, 657–662 (2007).

    Article 
    PubMed 

    Google Scholar 

  • Guan, J., Peske, J. D., Taylor, J. A. & Shastri, N. The nonclassical immune surveillance for ERAAP function. Curr. Opin. Immunol. 70, 105–111 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nagarajan, N. A., Gonzalez, F. & Shastri, N. Nonclassical MHC class Ib-restricted cytotoxic T cells monitor antigen processing in the endoplasmic reticulum. Nat. Immunol. 13, 579–586 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Doorduijn, E. M. et al. T cells engaging the conserved MHC class Ib molecule Qa-1b with TAP-independent peptides are semi-invariant lymphocytes. Front. Immunol. 9, 60 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Manoharan Valerio, M. et al. The promiscuous development of an unconventional Qa1b-restricted T cell population. Front. Immunol. 14, 1250316 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Geiger, K. M. et al. Murine cytomegalovirus downregulates ERAAP and induces an unconventional T cell response to self. Cell Rep. 42, 112317 (2023). This paper shows that downregulation of ERAAP by murine CMV results in the induction of T cells specific for Qa-1b presenting a similar self-peptide. The same Qa-1b-specific T cell population was observed in ERAAP-knockout mice by Nagarajan et al. (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Picker, L. J., Lifson, J. D., Gale, M. Jr., Hansen, S. G. & Früh, K. Programming cytomegalovirus as an HIV vaccine. Trends Immunol. 44, 287–304 (2023). This work provides a comprehensive review on the ability of CMV vectors to elicit MHC-E-restricted T cells.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Walker, B. D. CMV, MHC-E, and the quest for an unconventional AIDS vaccine. Sci. Immunol. 6, eabi5830 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Barry, P. A. et al. Cytomegalovirus-vectored vaccines for HIV and other pathogens. AIDS 34, 335–349 (2020).

    Article 
    PubMed 

    Google Scholar 

  • Früh, K. & Picker, L. CD8+ T cell programming by cytomegalovirus vectors: applications in prophylactic and therapeutic vaccination. Curr. Opin. Immunol. 47, 52–56 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Sylwester, A. W. et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J. Exp. Med. 202, 673–685 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kern, F. et al. Distribution of human CMV-specific memory T cells among the CD8pos. subsets defined by CD57, CD27, and CD45 isoforms. Eur. J. Immunol. 29, 2908–2915 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Masopust, D. & Picker, L. J. Hidden memories: frontline memory T cells and early pathogen interception. J. Immunol. 188, 5811–5817 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hansen, S. G. et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat. Med. 15, 293–299 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hansen, S. G. et al. Addendum: Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat. Med. 17, 1692 (2011).

    Article 
    CAS 

    Google Scholar 

  • Hansen, S. G. et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473, 523–527 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hansen, S. G. et al. Immune clearance of highly pathogenic SIV infection. Nature 502, 100–104 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hansen, S. G. et al. A live-attenuated RhCMV/SIV vaccine shows long-term efficacy against heterologous SIV challenge. Sci. Transl. Med. 11, eaaw2607 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hansen, S. G. et al. Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E. Science 351, 714–720 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hansen, S. G. et al. Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science 340, 1237874 (2013).

    Article 
    PubMed 

    Google Scholar 

  • Malouli, D. et al. Reevaluation of the coding potential and proteomic analysis of the BAC-derived rhesus cytomegalovirus strain 68-1. J. Virol. 86, 8959–8973 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Malouli, D. et al. Cytomegaloviral determinants of CD8+ T cell programming and RhCMV/SIV vaccine efficacy. Sci. Immunol. 6, eabg5413 (2021). This paper shows that multiple chemokine-like viral gene products independently prevent the induction of MHC-E-restricted T cells by CMV.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Malouli, D. et al. Cytomegalovirus-vaccine-induced unconventional T cell priming and control of SIV replication is conserved between primate species. Cell Host Microbe 30, 1207–1218.e7 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Malouli, D. et al. Human cytomegalovirus UL18 prevents priming of MHC-E- and MHC-II-restricted CD8+ T cells. Sci. Immunol. 9, eadp5216 (2024). This paper shows that HCMV UL18, a MHC-I-like LIR1 ligand, prevents the induction of MHC-E-restricted T cells when inserted into RhCMV.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Verweij, M. C. et al. Modulation of MHC-E transport by viral decoy ligands is required for RhCMV/SIV vaccine efficacy. Science 372, eabe9233 (2021). This study shows that viral VL9 peptides encoded in viral proteins are required for the induction of MHC-E-restricted T cells and that these T cells are required for protection against SIV.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hansen, S. G. et al. Evasion of CD8+ T cells is critical for superinfection by cytomegalovirus. Science 328, 102–106 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Powers, C., DeFilippis, V., Malouli, D. & Früh, K. Cytomegalovirus immune evasion. Curr. Top. Microbiol. Immunol. 325, 333–359 (2008).

    CAS 
    PubMed 

    Google Scholar 

  • Hansen, S. G. et al. Myeloid cell tropism enables MHC-E-restricted CD8+ T cell priming and vaccine efficacy by the RhCMV/SIV vaccine. Sci. Immunol. 7, eabn9301 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hansen, S. G. et al. Late gene expression-deficient cytomegalovirus vectors elicit conventional T cells that do not protect against SIV. JCI Insight 8, e164692 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hansen, S. G. et al. Cytomegalovirus vectors expressing Plasmodium knowlesi antigens induce immune responses that delay parasitemia upon sporozoite challenge. PLoS ONE 14, e0210252 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hansen, S. G. et al. Prevention of tuberculosis in rhesus macaques by a cytomegalovirus-based vaccine. Nat. Med. 24, 130–143 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Malouli, D. et al. Cytomegalovirus vaccine vector-induced effector memory CD4+ T cells protect cynomolgus macaques from lethal aerosolized heterologous avian influenza challenge. Nat. Commun. 15, 6007 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Burwitz, B. J. et al. MHC-E-restricted CD8+ T cells target hepatitis B virus-infected human hepatocytes. J. Immunol. 204, 2169–2176 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wang, Y. et al. Ad5-nCoV vaccination could induce HLA-E restricted CD8+ T cell responses specific for epitopes on severe acute respiratory syndrome coronavirus 2 spike protein. Viruses 16, 5 (2023).

    Article 

    Google Scholar 

  • Hogan, M. J. et al. Cryptic MHC-E epitope from influenza elicits a potent cytolytic T cell response. Nat. Immunol. 24, 1933–1946 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Walters, L. C. et al. Primary and secondary functions of HLA-E are determined by stability and conformation of the peptide-bound complexes. Cell Rep. 39, 110959 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Walters, L. C., McMichael, A. J. & Gillespie, G. M. Detailed and atypical HLA-E peptide binding motifs revealed by a novel peptide exchange binding assay. Eur. J. Immunol. 50, 2075–2091 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ruibal, P. et al. Discovery of HLA-E-presented epitopes: MHC-E/peptide binding and T-cell recognition. Methods Mol. Biol. 2574, 15–30 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Yang, H. et al. HLA-E-restricted SARS-CoV-2-specific T cells from convalescent COVID-19 patients suppress virus replication despite HLA class Ia down-regulation. Sci. Immunol. 8, eabl8881 (2023). This study shows that HLA-E-restricted, SARS-CoV-2-specific CD8+ T cells can be isolated and expanded from individuals with COVID-19.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Yang, H. et al. HLA-E-restricted, Gag-specific CD8+ T cells can suppress HIV-1 infection, offering vaccine opportunities. Sci. Immunol. 6, eabg1703 (2021). This paper shows that HLA-E-restricted HIV-specific T cells can be isolated and expanded from HIV-naive individuals.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ruibal, P. et al. Identification of HLA-E binding Mycobacterium tuberculosis-derived epitopes through improved prediction models. J. Immunol. 209, 1555–1565 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Paterson, R. L. et al. An HLA-E-targeted TCR bispecific molecule redirects T cell immunity against Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 121, e2318003121 (2024). This work determines that a bispecific antibody consisting of Mtb–HLA-E-specific TCR and anti-CD3 moieties can redirect T cells to M. tuberculosis-infected targeted cells.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wallace, Z. et al. Instability of the HLA-E peptidome of HIV presents a major barrier to therapeutic targeting. Mol. Ther. 32, 678–688 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lemberg, M. K., Bland, F. A., Weihofen, A., Braud, V. M. & Martoglio, B. Intramembrane proteolysis of signal peptides: an essential step in the generation of HLA-E epitopes. J. Immunol. 167, 6441–6446 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Weihofen, A., Lemberg, M. K., Ploegh, H. L., Bogyo, M. & Martoglio, B. Release of signal peptide fragments into the cytosol requires cleavage in the transmembrane region by a protease activity that is specifically blocked by a novel cysteine protease inhibitor. J. Biol. Chem. 275, 30951–30956 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Bland, F. A., Lemberg, M. K., McMichael, A. J., Martoglio, B. & Braud, V. M. Requirement of the proteasome for the trimming of signal peptide-derived epitopes presented by the nonclassical major histocompatibility complex class I molecule HLA-E. J. Biol. Chem. 278, 33747–33752 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Coupel, S. et al. Expression and release of soluble HLA-E is an immunoregulatory feature of endothelial cell activation. Blood 109, 2806–2814 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Hengel, H. et al. A viral ER-resident glycoprotein inactivates the MHC-encoded peptide transporter. Immunity 6, 623–632 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Ahn, K. et al. The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP. Immunity 6, 613–621 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Park, B. et al. Human cytomegalovirus inhibits tapasin-dependent peptide loading and optimization of the MHC class I peptide cargo for immune evasion. Immunity 20, 71–85 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Prod’homme, V. et al. Human cytomegalovirus UL40 signal peptide regulates cell surface expression of the NK cell ligands HLA-E and gpUL18. J. Immunol. 188, 2794–2804 (2012).

    Article 
    PubMed 

    Google Scholar 

  • Davis, Z. B. et al. A conserved HIV-1-derived peptide presented by HLA-E renders infected T-cells highly susceptible to attack by NKG2A/CD94-bearing natural killer cells. PLoS Pathog. 12, e1005421 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hannoun, Z. et al. Identification of novel HIV-1-derived HLA-E-binding peptides. Immunol. Lett. 202, 65–72 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Romero-Martin, L. et al. Disruption of the HLA-E/NKG2X axis is associated with uncontrolled HIV infections. Front. Immunol. 13, 1027855 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Peppa, D. et al. Adaptive reconfiguration of natural killer cells in HIV-1 infection. Front. Immunol. 9, 474 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Guma, M. et al. Human cytomegalovirus infection is associated with increased proportions of NK cells that express the CD94/NKG2C receptor in aviremic HIV-1-positive patients. J. Infect. Dis. 194, 38–41 (2006).

    Article 
    PubMed 

    Google Scholar 

  • Mela, C. M. et al. Switch from inhibitory to activating NKG2 receptor expression in HIV-1 infection: lack of reversion with highly active antiretroviral therapy. AIDS 19, 1761–1769 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Mela, C. M. & Goodier, M. R. The contribution of cytomegalovirus to changes in NK cell receptor expression in HIV-1-infected individuals. J. Infect. Dis. 195, 158–159 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Maidji, E., Somsouk, M., Rivera, J. M., Hunt, P. W. & Stoddart, C. A. Replication of CMV in the gut of HIV-infected individuals and epithelial barrier dysfunction. PLoS Pathog. 13, e1006202 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Jost, S. et al. Antigen-specific memory NK cell responses against HIV and influenza use the NKG2/HLA-E axis. Sci. Immunol. 8, eadi3974 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hasan, M. Z. et al. SARS-CoV-2 infection induces adaptive NK cell responses by spike protein-mediated induction of HLA-E expression. Emerg. Microbes Infect. 13, 2361019 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Hammer, Q. et al. SARS-CoV-2 Nsp13 encodes for an HLA-E-stabilizing peptide that abrogates inhibition of NKG2A-expressing NK cells. Cell Rep. 38, 110503 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Alrubayyi, A. et al. Natural killer cell responses during SARS-CoV-2 infection and vaccination in people living with HIV-1. Sci. Rep. 13, 18994 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Huot, N. et al. SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells. Nat. Immunol. 24, 2068–2079 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Vietzen, H. et al. Torque teno viruses exhaust and imprint the human immune system via the HLA-E/NKG2A axis. Front. Immunol. 15, 1447980 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Vietzen, H. et al. HLA-E-restricted immune responses are crucial for the control of EBV infections and the prevention of PTLD. Blood 141, 1560–1573 (2022).

    Article 
    PubMed Central 

    Google Scholar 

  • Vietzen, H., Hartenberger, S., Aberle, S. W. & Puchhammer-Stöckl, E. Dissection of the NKG2C NK cell response against Puumala orthohantavirus. PLoS Negl. Trop. Dis. 15, e0010006 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Antrobus, R. D. et al. Virus-specific cytotoxic T lymphocytes differentially express cell-surface leukocyte immunoglobulin-like receptor-1, an inhibitory receptor for class I major histocompatibility complex molecules. J. Infect. Dis. 191, 1842–1853 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Wu, H. L. et al. The role of MHC-E in T cell immunity is conserved among humans, rhesus macaques, and cynomolgus macaques. J. Immunol. 200, 49–60 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Picker, L. J., Hansen, S. G. & Lifson, J. D. New paradigms for HIV/AIDS vaccine development. Annu. Rev. Med. 63, 95–111 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  • Pfeiffer, T. et al. Posoleucel, an allogeneic, off-the-shelf multivirus-specific T-cell therapy, for the treatment of refractory viral infections in the post-HCT setting. Clin. Cancer Res. 29, 324–330 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

Continue Reading

  • Scrolling on the toilet increases your risk of haemorrhoids, new study shows

    Scrolling on the toilet increases your risk of haemorrhoids, new study shows

    Many of us are guilty of scrolling our smartphones on the toilet. But a new study from the United States, published today, has found this habit may increase your risk of developing haemorrhoids by up to 46%.

    So, what’s the link? How can time on your phone lead to these painful lumps in and around your anus? Here’s what we know.

    What are haemorrhoids?

    Every healthy person has haemorrhoids, sometimes called piles. They are columns of cushioned tissue and blood vessels found close to the opening of the anus.

    We don’t notice haemorrhoids until they’re symptomatic.
    Aleksandr Kharitonov/Getty

    Haemorrhoids have a really important role in maintaining bowel continence or, to put it simply, keeping your poo in.

    When all is well, we don’t notice them. But haemorrhoids can get swollen and this can lead to symptoms such as pain, bleeding or feeling a lump just inside your anus (internal haemorrhoids) or protruding outside (external haemorrhoids).

    So when someone “has haemorrhoids”, it means they have become inflamed or symptomatic.

    This is extremely common: more than one in two of us will experience symptomatic haemorrhoids at some point in our lives.

    You are more likely to get haemorrhoids if you:

    • are older (over 45)
    • are pregnant
    • are overweight
    • have persistent constipation or diarrhoea
    • regularly lift heavy objects
    • spend a lot of time on the toilet.

    The link between toilet time and haemorrhoids

    Prolonged sitting in general has not been linked to developing haemorrhoids.

    However, a standard toilet seat – unlike a chair or couch – has a large internal opening that provides no support for the pelvic floor (the group of muscles and ligaments that support the bladder, bowel and uterus).

    Prolonged sitting on a toilet seat is believed to increase pressure inside the pelvic floor and lead to blood pooling in the vascular cushions of the anus. This makes haemorrhoids more likely to develop.

    What the new study looked at

    The new US study recruited 125 adults, aged 45 and older, who were undergoing a colonoscopy at Beth Israel Deaconess Medical centre.

    Researchers surveyed them about their smartphone habits while using the toilet, including how often they checked their phone and for how long. Participants also reported on other behaviours such as straining, their fibre intake, and how much physical activity they did.

    The researchers recorded whether they had haemorrhoids. Since the participants were all having a colonoscopy, the presence of internal haemorrhoids could be directly confirmed visually.

    What did the study show?

    Two-thirds (66%) of all participants used smartphones while on the toilet. The most common activity was reading news (54.3%), followed by social media (44.4%).

    Those who used their smartphones spent longer on the toilet than those who didn’t. More than one in three (37.3%) toilet smartphone users spent over five minutes on the toilet, compared to just over one in 20 (7%) of those who didn’t use their smartphones.

    The smartphone users had a 46% higher risk of haemorrhoids, compared to those who didn’t use their smartphone. To calculate this, researchers took into account other known risk factors for haemorrhoids such as gender, age, body mass index, exercise activity, straining and fibre intake.

    However, unlike some other research, this study did not find a link between straining and haemorrhoids.

    As a result, the researchers concluded that time spent on the toilet poses a more significant risk for haemorrhoids than straining. However, we can’t rule out straining as a risk factor, based on one study.

    Some other limitations to consider

    The study relied on participants remembering whether or not they strained, and how long they spent on the toilet.

    This kind of recall is subjective, and may also be influenced by taking part in the study. For example, if the participants thought they had haemorrhoids, they may be more likely to report straining.

    The study’s small sample size and the participants’ age (all over 45) also mean it is unlikely to be representative of the broader population.

    Toilet sitting time

    The new study is not the first to study the link between time spent on the toilet and developing haemorrhoids. In 2020, a Turkish study found spending more than five minutes on the toilet was associated with haemorrhoids.

    Another 2020 study from Italy of 52 people with diagnosed internal or external haemorrhoids noted the longer they spent on the toilet, the more severe their haemorrhoids.



    Read more:
    Do men really take longer to poo?

    So, what are we doing on the toilet?

    Defaecation itself usually doesn’t take long. One study found it took healthy adults an average two minutes when sitting, but only 51 seconds when squatting.

    The majority of “toilet sitting time” usually means just that – sitting on the toilet, doing other activities aside from pooing (or weeing).

    One 2008 study from Israel surveyed 500 adults and found more than half (52.7%) read books or newspapers while on the toilet. It also found toilet readers spent significantly more time on the toilet.

    How to avoid haemorrhoids

    The usual advice is to increase the amount of fibre in your diet (eating more fruit, vegetables and wholegrains) and ensure you drink enough water. This makes it easier to pass a stool and reduces straining – which you should also try to avoid.

    However, the new research confirms previous evidence that cutting down toilet sitting time may also help. So, avoiding distractions by leaving your smartphone outside the bathroom is a good idea (and as a bonus, will expose your device to fewer germs).



    Read more:
    Your phone is covered in germs: a tech expert explains how to clean it without doing damage

    If you have any concerning symptoms, such as blood in your stool, a new lump in the anal region, or pain when passing a bowel motion then you should see your local doctor for further investigations and treatment.

    Continue Reading