Immune Checkpoint Inhibitors, Cardiovascular Health, and a Potentially Protective Biomarker

New research out of Spain has shown that patients with cancer who had lower levels of the biomarker CD69 (receptor on T cells) before starting treatment with immune checkpoint inhibitors (ICIs) had a more negative immune response and were at higher risk of cardiovascular damage and myocarditis.¹ Although more work is needed to validate this potentially cardioprotective biomarker, these study findings may indicate the need to monitor this population more closely and may help researchers develop new treatments to prevent the immune dysregulation seen in these patients.

“Immune checkpoint inhibitors have revolutionized cancer treatment, but they can also damage the hearts of some patients,” stated Pilar Martín, PhD, who presented these findings at the 2025 European Society of Cardiology (ESC) Cardio-Oncology Annual Conference in Florence, Italy. “In this study, we monitored how levels of immune cells, which are known to be involved in the development of heart diseases, change after treatment.” Dr. Martín is Assistant Professor and Head of the Regulatory Molecules of Inflammation Lab at the Spanish National Center for Cardiovascular Research (CNIC), Madrid, and group leader at CIBER-CV (Center for Biomedical Network Research Cardiovascular).

“We were surprised to see an early and rapid loss of protective immune cells (regulatory T cells) after cancer patients started treatment,” she added. “This suggests a window of vulnerability early in treatment.”

Background

Among the cardiovascular toxicities associated with immune checkpoint inhibitors are cardiomyopathy, pericarditis, arrhythmia, conduction abnormalities, and myocarditis. And, according to Dr. Martín, it is “just the tip of the iceberg,” with more novel therapies emerging.

In an observational cohort study of more than 2,600 adults who received at least one dose of an immune checkpoint inhibitor, 27 (1%) were diagnosed with immune checkpoint inhibitor–induced myocarditis.² The investigators noted that at diagnosis, these individuals had elevated levels of high-sensitivity troponin T, alanine aminotransferase, aspartate aminotransferase, and creatine phosphokinase (CPK). “An increase in noncardiac biomarkers during ICI treatment, notably CPK, should prompt further evaluation for ICI myocarditis,” they concluded.

“Myocarditis is one of the most lethal secondary effects of immune checkpoint inhibitors,” noted Dr. Martín. In fact, a retrospective cohort study of 160 patients with suspected immune checkpoint inhibitor–induced myocarditis at Massachusetts General Brigham Health System revealed that severe ICI-induced myocarditis (n = 28) was linked to increased 1-year cardiovascular mortality.³ However, 1-year cardiovascular hospitalization rate and long-term left ventricular ejection fraction were similar across all groups (severe, nonsevere, negative).

Dr. Martín also mentioned the importance of tracking the dynamics of cardiac troponins in patients with different tumors treated with immune checkpoint inhibitors.⁴ Among the cardiovascular assessments for such patients are history, presentation, physical exam; ECG and biomarkers; echocardiography with global longitudinal strain; cardiac MRI with parametric mapping; and pathology.

Study Details

In the prospective cohort substudy, the investigators analyzed blood samples from 215 patients with cancer from the Spanish Immunotherapy Registry of Cardiovascular Toxicity (SIR-CVT) before treatment and at four other intervals: at 2 to 4 weeks; 10 to 12 weeks; 6 months; and 1 year after treatment with immune checkpoint inhibitors. A total of 19 centers participated in this study, with an estimated sample size of 500 patients within 12 months. And at the 2025 ESC-Cardio-Oncology meeting, Dr. Martín presented the results from the first 215 patients.

“Those with lower expression of CD69 had a twofold higher risk of cardiovascular disease than did those with higher expression of CD69.”

— PILAR MARTÍN, PhD

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The goals of the study are to register risk factors and daily practice management of cardiovascular toxicity in patients with solid organ cancer receiving immune checkpoint inhibitors; define clinical, ECG, imaging, laboratory, and genetic markers for early diagnosis of cardiotoxicity; study the immunologic profile of patients on immune checkpoint inhibitors and the potential of human microRNA (miR-721) as a biomarker for early diagnosis of immune checkpoint inhibitor–induced myocarditis⁵; and evaluate the impact of cardiac monitoring on the reduction of inappropriate treatment suspensions.

Patients had a range of different cancers, including non–small cell lung cancer (57%), breast cancer (7%), and melanoma (7%), and were treated with different types of immune checkpoint inhibitors (PD-1, PD-L1, and CTLA-4). Median patient age was 68; 68% were male, 83% had at least one cardiovascular risk factor, and 32% has previous cardiac disease. The phenotyping before the initiation of immunotherapy included biomarkers such as cardiovascular magnetic resonance, ecologic (environmental stressor’s impact), troponin plus B-type natriuretic peptide, ECG, and miR-721.

The focus was on T regulatory cells (CD4+FOXP3+CD69+) and proinflammatory Th17 cells (CD4+IL-17+). Based on CD69 expression, patients were stratified into high- and low-risk groups for cardiovascular diseases. “We know that the ligands that activate this molecule are very much related to cardiovascular disease,” said Dr. Martín. Changes in the levels of the patients’ immune cell populations were monitored over time.

Key Results

During the assessment of CD4-positive cells, they were separated into memory and naive cells. In brief, the memory CD4-positive T cells are long-lived antigen-specific T cells, whereas naive cells are mature T cells that have not yet encountered their specific antigen. In the CD4-gated populations, within the first week after immune checkpoint inhibitor therapy was initiated, “we see how the percentage of CD4-positive memory cells declines and the percentage of CD4-positive naive cells rise[s],” commented Dr. Martín. “And the same more or less can be seen with the T regulatory cells–gated populations.”

In addition, Dr. Martín noted, patients who had lower baseline CD69 expression experienced a pronounced decline, “suggesting increased susceptibility to cardiovascular toxicity.” Such a decline in these protective immune cells has previously been linked to a higher risk of developing cardiovascular complications such as myocarditis.⁶

Finally, an increase in cytotoxic CD8-positive T cells after 3 weeks was noted, and this change became significant at weeks 11 and 26 after immune checkpoint inhibitor therapy. “For me, the more interesting data are the drop in the T regulatory cells’ expression of CD69 during the 3 first weeks after immune checkpoint inhibitor treatment, indicating a loss of peripheral immune tolerance,” Dr. Martin said. “And most patients experienced a steady increase in Th17 cells after immune checkpoint inhibitor treatment after 1 year.”

Clinical Implications of Distinct Immune Profiles

Upon bioinformatic analysis, the study authors confirmed distinct immune profiles between those at high and low risk of immunotherapy-related cardiovascular disease. “We saw these groups had very different response to the cancer treatments,” stated Dr. Martín. “Those who had lower levels of CD69 before starting treatment had a more negative immune response, which puts them at much greater risk of heart damage.” In fact, those with lower expression of CD69 had a twofold higher risk of cardiovascular disease than did those with higher expression of CD69, she added.

The study authors believe these results may pave the way for personalized strategies to stratify patients by CD69 expression to potentially identify those at higher risk of developing cardiovascular toxicity when undergoing treatment with immune checkpoint inhibitors. “Analysis of the immunologic phenotype of patients before starting immunotherapy is very important,” Dr. Martín concluded.

DISCLOSURE: Dr. Martín reported no conflicts of interest.

REFERENCES

1. Martín P, Ortega-Sollero E, Ruiz-Fernandez I, et al: Immune profiling of cancer patients in the Spanish Immunotherapy Registry of Cardiovascular Toxicity (SIR-CVT). 2025 ESC Cardio-Oncology Annual Conference. Presented June 20, 2025.
2. Vasbinder A, Chen YA, Procureur A, et al: Biomarker trends, incidence, and outcomes of immune checkpoint inhibitor-induced myocarditis. JACC CardioOncol 4:689-700, 2022.
3. Ben Zadok OI, Levi A, Divakaran S, et al: Severe vs nonsevere immune checkpoint inhibitor-induced myocarditis: Contemporary 1-year outcomes. JACC CardioOncol 5:732-744, 2023.
4. Zatarain-Nicolás E, Martín P, Rodas IM, et al: Cardiovascular toxicity of checkpoint inhibitors: Review of associated toxicity and design of the Spanish Immunotherapy Registry of Cardiovascular Toxicity. Clin Transl Oncol 25:3073-3085, 2023.
5. Blanco-Domínguez R, Sánchez-Díaz R, de la Fuente H, et al: A novel circulating microRNA for the detection of acute myocarditis. N Engl J Med 384:2014-2027, 2021.
6. Cruz-Adalia A, Jiménez-Borreguero LJ, Ramírez-Huesca M, et al: CD69 limits the severity of cardiomyopathy after autoimmune myocarditis. Circulation 122:1396-1404, 2010.