Immunotherapy-associated myocarditis associated with T cells targeting cardiac-specific antigens

Myocarditis (inflammation of the heart muscle) is a rare but potentially fatal complication of immune checkpoint inhibitor (ICI) cancer immunotherapy. Researchers at the Vanderbilt-Ingram Cancer Center found that the mechanism of this serious adverse event involved her T cells that recognize the cardiac antigen alpha-myosin. The team notes that findings from experiments in mice and studies using blood cells from patients with ICI-associated myocarditis (ICI-MC) may help scientists identify biomarkers. suggesting. Resistant to immunotherapy.

The researchers, led by Dr. Justin Barko, Ingram Associate Professor of Cancer Research at Vanderbilt Ingram Cancer Center, Naturein a paper titled “”α-Myosin-specific T cells drive immunotherapy-associated myocarditisIn their report, the research team noted that identifying alpha-myosin as an autoantigen “…may lead to the identification of a biomarker to predict which patients are at increased risk for myocarditis.” concluded. – Pre-existing autoantibodies.

Immune checkpoint inhibitor therapy has changed the landscape of cancer treatment and prognosis, but not all patients respond and many experience immune-related adverse events (irAEs), especially with ICIs. It’s noticeable when you do,” the authors said. Also, ICI-associated myocarditis is rare, affecting less than 1% of her immunotherapy patients, but with a mortality rate of nearly 50%. “Immune-related adverse events, particularly severe toxicities such as myocarditis, are a major challenge to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy,” continued the researchers.

Clinicians still do not have a clear understanding of why some patients develop immunotherapy-associated myocarditis. Early treatment with steroids can improve survival, but more effective treatments are urgently needed. increase. “Currently, clinically actionable biomarkers of response and toxicity are limited, and the mechanistic basis for irAEs is poorly defined.”

In 2016, the Balko group first reported two immunotherapy-treated melanoma patients who developed myocarditis, and the researchers conducted several experiments. early research We link cardiac T-cell activity to this condition. “Then, in Houston, he worked with Nobel laureate James P. Allison, Ph.D., at MD Anderson Cancer Center, to mouse model It seemed to replicate what we observed in our patients,” said Balko. “Using the same model, I worked with Douglas Johnson, M.D., Ph.D., an oncologist at MSCI, Vanderbilt University, and co-corresponding author Javid Moslehi, M.D., UCSF, to determine the mechanisms of why it occurs. Importantly, we were able to translate this to patients, and this finding represents the next important step in making these often effective treatments safer for patients.”

For the newly reported study, the research team obtained heart samples and peripheral blood from three patients who suffered from severe myocarditis after being treated with immune checkpoint inhibitors. These samples were analyzed after the team recreated immunotherapy-associated myocarditis in a mouse model. “Pdcd1^–/–Ctla4^+/– Mice recapitulate clinicopathologic features of ICI-MC, including myocardial T-cell infiltration,” they explained.

Researchers sequenced individual T cells that invade the heart during myocarditis in a mouse model and reconstructed their receptors. These T cell receptors (TCRs) were then screened against peptides to determine specificity. “In our mouse model, we found that myocarditis is characterized by highly clonal TCR-bearing cytotoxic CD8+ T cells, and that his CD8+ cells are required for the development of myocarditis.” showed,” the authors explain. “The three most clonally related TCRs from independent mice recognized alpha-myosin epitopes.” When the researchers then analyzed human samples, three patients had cardiac and skeletal We found that there are also reactive T cells for α-myosin that are only expressed in muscle. “Establishing the CD8+ T cells required for disease, he identifies alpha-myosin as the most abundant cognate antigen of the TCR in myocarditis,” the team said. “Furthermore, we extend these findings to human disease and show that an α-myosin expanded TCR is present in inflamed cardiac and skeletal muscle of ICI-MC patients.”

“The extension of our findings from mouse models to human patients has been an important part of our work,” said lead author, a Ph.D. student in the Vanderbilt Medical Scientist Training Program at Barco Laboratories. commented Dr. Margaret Axelrod of These results demonstrate how mouse models can be useful for making initial discoveries and using them to understand something about human disease. Our data indicate that α-myosin is a disease-associated autoantigen in patients with immunotherapy-associated myocarditis. We hope that understanding the mechanisms of this often fatal complication will pave the way for making immunotherapy safer for patients. ”

This study is the first to identify a role for α-myosin in the mechanism of cardiac complications from immune checkpoint inhibitors and one of the first to identify candidate autoantigens for immunotherapy toxicity in humans. “These studies highlight the critical role of cytotoxic CD8+ T cells, identify candidate autoantigens in ICI-MC, and provide new insights into the pathogenesis of ICI toxicity.” Provides insight … Knowledge of the most relevant disease antigens may facilitate antigen-directed approaches to suppress inflammation without compromising anti-tumor efficacy such as tolerogenic vaccines.”

Balco added. “Autoreactive T cells are the putative mechanism of many toxicity to immunotherapies, with specific T cell receptors (often unique to each patient) and antigen sources (tens to hundreds of thousands of potential It’s been pulled from antigens), and the human body) is hard work.”