High Levels of CD163+ Tumor-Associated Macrophages Could Improve Outcomes With Nivolumab in Metastatic RCC

The efficacy of PD-1 blockade could be partially mediated by reprogramming tumor-associated macrophages (TAMs) from a pro-tumorigenic to an anti-tumorigenic state, as high levels of CD163-positive TAMs are associated with improved outcomes to anti–PD-1 therapy in metastatic clear cell renal cell carcinoma (ccRCC), according to Berkay Simsek, MD.¹

During a presentation at the 2025 Kidney Cancer Research Summit, Simsek outlined the goals of assessing the association of CD163-positive TAMs with clinical outcomes to first-line nivolumab (Opdivo) in metastatic ccRCC, and to investigate whether TAMs and exhausted CD8-positive tumor-infiltrating lymphocytes (TILs) are located and interact within a “spatially defined niche.”

Simsek is a research fellow in Pathology at the Brigham and Women’s Hospital in Boston, Massachusetts.

The Role of TAMs in RCC and Methods of Investigation

TAMs promote immune suppression in the tumor microenvironment, despite having a reputation for being associated with resistance to immune checkpoint inhibitors in other cancer types, including colorectal cancer and pancreatic ductal adenocarcinoma, along with observed responses in Hodgkin lymphoma, Simsek explained in the presentation. Nevertheless, “the role [of TAMs] as predictors of clinical outcomes still remains somewhat unclear,” he noted.

Furthermore, TAMs promote T-cell exhaustion based on observations from preclinical models.

“Chemokines released from activated T cells cause recruitment of monocytes from blood circulation into [the] TME, and those monocytes develop into differentiated macrophages,” Simsek stated. “Later on, ineffective antigen presentation as well as immunosuppressive ligand-receptor interactions between TAMs and TILs, coupled with the secretion of immunosuppressive cytokines into the TME, cause exhaustion of cytotoxic T cells and diminish their ability to mount an effective response against the tumor.”

Simsek noted that the first method to investigate the respective goals was to analyze pretreatment tumor samples from 67 patients who were enrolled in the phase 2 HCRN GU16-260 trial (NCT03117309), which evaluated first-line nivolumab in patients with metastatic ccRCC.

HCRN GU16-260 also examined the association between PD-1 expression on tumor-infiltrating regulatory T cells (Tregs) and resistance to first-line nivolumab in advanced ccRCC.² Of note, the percentage of PD-1–positive Tregs did not have a statistically significant association with progression-free survival (PFS; HR, 2.62; P = .169) or objective response rate (ORR; odds ratio [OR], 0.72; P = .42).

“To identify TAMs and CD8-positive TILs in various states of exhaustion, we utilized the workflow previously developed in our lab based on multiplex immunofluorescent stain in the tissue. We identified CD163-positive TAMs [and] non-terminal exhausted CD8-positive TILs as the cells defined with co-expression of CD8 and PD-1, but negative for TIM3 and LAG3, and terminally exhausted CD8-positive TILs, with cells defined with co-expression of CD8, PD-1, and either TIM3 or LAG3,” Simsek reported.

Additionally, in the second method, investigators assessed statistical and bioinformatics analyses to help inform the aims to observe potential associations of density of CD163-positive TAMs with PFS and ORR that were assessed via univariable Cox and logistic regression models, respectively.¹ Another aim included a spatial proximity analysis that was performed using the “sf” package within the R software.

Efficacy Data Using Density of CD163-Positive TAMs With First-Line Nivolumab

Based on the efficacy data, focusing on the density of CD163-positive TAMs with first-line nivolumab in patients with metastatic ccRCC, the unadjusted and adjusted for International Metastatic RCC Database Consortium risk group (favorable vs poor/intermediate) ORs for ORR were 2.21 (95% CI, 1.33-3.69; P = .002) and 2.58 (95% CI, 1.43-4.64; P = .002), respectively. Moreover, the unadjusted and adjusted PFS ORs were 0.77 (95% CI, 0.61-0.97; P = .029) and 0.78 (95% CI, 0.62-0.98; P = .032), respectively.

Additionally, a high density of CD163-positive TAMs was associated with improved ORR and PFS on first-line nivolumab. Specifically, among patients with a high density (n = 34), 65% achieved a response compared with 15% of patients who had low density (n = 5/33; P < .001). The median PFS was 16.6 months (95% CI, 5.5-32.9) vs 5.5 months (95% CI, 4.1-10.6) in patients with high and low density, respectively (P = .009).

Spatial Proximity Analysis and the Role of Exhausted CD8-Positive TILs

Regarding the spatial proximity analysis, Simsek noted that the density of terminally exhausted CD8-positive TILs and the density of non-terminally exhausted CD8-positive TILs were determined within a 30 µm radius area that focused on CD163-positive TAMs—determined as the proximal area—and outside of this area, which was the non-proximal area.

“[We examined the] areas and for both exhausted TIL subsets, we calculated their enrichment levels in the proximal vs non-proximal areas, and compared their enrichment levels with each other,” Simsek explained.

The densities of TILs in the proximal and non-proximal areas of TAMs were compared, and investigators established that the density of non-terminally exhausted CD8-positive TILs was higher in areas that were proximal to TAMs vs their densities in non-proximal areas to TAMs, he reported.

“Both terminally exhausted TIL subsets were enriched in proximity of the CD163-positive TAMs, but when we compared their enrichment levels, we observed that enrichment levels for terminally exhausted CD8-positive TILs in proximity of the CD163-positive TAMs were significantly higher compared to the enrichment levels of non-terminally exhausted CD8-positive TILs,” Simsek concluded.

Disclosures: Simsek had no relevant disclosures to report.

References

1. Simsek S. CD163+ tumor-associated macrophages and clinical outcomes to first-line nivolumab therapy in patients with metastatic clear cell renal cell carcinoma: insights from the HCRN GU16-260 trial. Presented at: 2025 Kidney Cancer Research Summit; July 17-18, 2025; Boston, Massachusetts.
2. Mohanna R, Simsek B, El Ahmar N, et al. Association between PD-1 expression on tumor-infiltrating regulatory T cells and resistance to first-line nivolumab in advanced clear cell renal cell carcinoma: insights from the HCRN GU16-260 clinical trial. J Clin Oncol. 2025;43(suppl 5):590. doi:10.1200/JCO.2025.43.5_suppl.590