New Developments in Understanding Link Between Immune Checkpoint Inhibition and Myocarditis

Myocarditis, a dangerous form of heart inflammation, can develop in patients treated with immune checkpoint inhibitors for cancer. A study led by physicians and scientists at the Broad Institute of MIT, Harvard, and Massachusetts General Hospital has uncovered that the immune basis of this inflammation is changes in specific types of immune and stromal cells in the heart can indicate underlying myocarditis. They also pinpointed factors in the blood that may indicate whether a patient’s myocarditis is likely to lead to morbidity.

The study was published in Nature, and results are among the earliest translational findings to come from the Sever Immunotherapy Complications Service and Clinical-Translational Research Effort, which is based at Mass General Cancer Center. The team leading this project focused on myocarditis as one of their first research projects because despite its rarity, it is the adverse event with the highest morbidity rate related to immune checkpoint inhibition.

These findings provide the first evidence of immune reaction in the heart that is distinct from the response in the tumor, thus suggesting that targeted treatments may address myocarditis while allowing patients to continue receiving potentially life-saving antitumor immunotherapy.

Roughly 1% of patients treated with an immune checkpoint inhibitor, which amounts to more than 2,000 individuals per year, will develop myocarditis, with that percentage reaching nearly 2% among patients treated with certain immunotherapy combinations. The morbidity of myocarditis lies in events such as arrhythmia and heart failure in 50% of cases, and about one third of people who develop myocarditis will die from it despite current treatments.

Methodology and Findings

The researchers collected blood samples from individuals who developed myocarditis while on an immune checkpoint inhibitor and in the lab, single-cell RNA sequencing analysis along with microscopy, proteomic analysis, and T-cell receptor sequencing were performed to identify which cells are involved in the driving and sustaining inflammation in myocarditis.

The researchers also collected heart and tumor tissue samples from some of the patients. In the heart tissue, they observed the upregulation of molecular pathways to recruit and retain immune cells involved in inflammation. There was also an increased abundance of several immune cell subsets as well as increase in abundances of certain cellular groupings composed of specific cytotoxic T cells, conventional dendritic cells, and inflammatory fibroblasts. In the blood, there were reductions in plasmacytoid dendritic cells, conventional dendritic cells, and B-lineage cells as well as an increased number of other mononuclear phagocytes.

Of note, the T-cell receptors that were abundant in the affected heart tissue samples were distinct from the T-cell receptors found in the tumor samples, which is a novel discovery. It was previously thought that the immune responses in the heart and tumor were the same. There was also no evidence found of T-cell receptors recognizing the α-myosin protein, which was previously reported to be a pivotal antigen driving immunotherapy myocarditis.

The pattern of T-cell subtypes in the blood was also predictive of which individuals were more likely to develop myocarditis; this blood-based measurement could one day be used as a marker to flag patients at higher risk who may need additional monitoring.

“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,” co-first author Steven Blum, an oncologist at MGH and postdoctoral fellow in the Villani lab, noted.