Researchers have identified key immune mechanisms driving myocarditis in cancer patients treated with immune checkpoint inhibitors, offering potential targets for more effective and less toxic therapies. The study, published in Nature, reveals distinct immune cell populations and molecular pathways active in the hearts of these patients, providing a foundation for developing targeted treatments that could allow patients to continue life-saving immunotherapy.
Myocarditis, a severe inflammation of the heart, affects approximately 1% of patients treated with immune checkpoint inhibitors, with the incidence rising to nearly 2% in those receiving combination immunotherapy. This condition leads to dangerous cardiac events in 50% of cases and a mortality rate of around 33%, highlighting a critical unmet need for effective treatments. Current approaches, such as broad immunosuppression with steroids, can compromise the efficacy of the cancer therapy itself.
Unraveling the Immune Response
To understand the underlying mechanisms, researchers collected blood and heart tissue samples from patients who developed myocarditis during immune checkpoint inhibitor therapy. Using single-cell RNA sequencing, microscopy, and proteomic analysis, they identified specific immune cell subsets and molecular pathways involved in the inflammatory process.
"Since we first started seeing [immune] checkpoint [inhibitor–related] myocarditis less than a decade ago, it’s largely been a black box," said Dr. Daniel Zlotoff, a lead author of the study. "Only now are we starting to answer the fundamental biological questions, which we hope will shed light on the optimal treatments to make it more tolerable and improve outcomes for patients."
The analysis revealed an upregulation of molecular pathways that recruit and retain immune cells in the heart tissue. Researchers observed an increased abundance of cytotoxic T cells, conventional dendritic cells, and inflammatory fibroblasts clustered together in the hearts of patients with active myocarditis. In the blood, they noted reductions in plasmacytoid dendritic cells, conventional dendritic cells, and B-lineage cells, along with increased numbers of other mononuclear phagocytes.
Distinct Immune Responses in Heart and Tumor
Notably, the study found that T-cell receptors abundant in the affected heart tissue differed from those found in tumors. This contrasts with previous assumptions that the immune responses in the heart and tumor were the same. Furthermore, the researchers found no evidence of T-cell receptors recognizing alpha-myosin, a protein previously implicated in immune checkpoint inhibitor-related myocarditis. This suggests that the T-cell receptors in the heart recognize other, as-yet-undetermined antigens.
Predicting Mortality Risk
The study also identified patterns of T-cell subtypes in the blood that correlated with the likelihood of death from myocarditis. This finding suggests that a blood-based measurement could potentially identify patients at increased risk, allowing for closer monitoring or alternative treatment strategies. "This work provides a biological foundation for testing more targeted therapies for myocarditis [caused by] an immune checkpoint inhibitor...[and may] lead to improved outcomes," noted Dr. Tomas Neilan, a senior author of the study.
Implications for Treatment and Future Research
The discovery of distinct immune responses in the heart and tumor offers hope for developing targeted therapies that can address myocarditis without compromising the antitumor effects of immunotherapy. The findings also support the rationale for ongoing clinical trials, such as the ATRIUM trial (NCT05335928), which is evaluating the use of abatacept, an arthritis drug, to control myocarditis in these patients.
"Because the responses in the tumor and the heart are different, it makes us hopeful that we can someday disentangle the two and treat them separately," said Dr. Steven Blum, a lead author of the study. Future research will focus on identifying the specific antigens involved in the immune response in the heart and tumor, which could lead to the development of even more targeted and effective therapies.
