Translational approach to study pathophysiological mechanisms and find out prognostic factors of immune checkpoint inhibitors-induced myocarditis

Introduction Immune checkpoint inhibitors (ICIs) are widely used in cancer therapy but can trigger severe immune-related adverse events, including myocarditis (ICI-M), a potentially life-threatening condition. While early detection of ICI-M has recently reduced mortality, its underlying pathophysiology remains poorly understood. Emerging clinical and preclinical studies suggest a pivotal role for T cells in disease onset, yet the precise mechanisms driving myocardial inflammation remain to be elucidated. Objective Developing a translational approach to characterize the pathophysiological mechanisms and to identify prognostic factors of ICI-M to improve patient management. Method We prospectively collect clinical, biological, and cardiac imaging data from patients before and during treatment with ICIs. Peripheral blood mononuclear cells (PBMCs) and induced pluripotent stem cell (hiPSC)-derived cardiac cells from the same selected patients serve as models to explore cellular and molecular mechanisms. A preclinical mouse model is used to analyze in vivo cardiac function and to complement molecular and cellular analyses. PBMCs are collected before ICIs, during ICI-M management, and three months post-treatment in non-ICI-M patients. We generate hiPSC-derived endothelial cells and cardiomyocytes from 3 representative ICI-M and non-ICI-M patients. CD4+/CD8+ T cells are isolated for RNA sequencing and functional analyses, and co-cultured with hiPSC-derived cardiac cells to establish an in vitro cardiotoxicity model. Results We identified specific protein signatures in CD8+ T cells from ICI-M patients, notably increased interferon-gamma (IFN-γ) production. Activation of the NLRP3 inflammasome, in response to IFN-γ treatment, was observed in hiPSC-derived endothelial cells and cardiomyocytes from patients. Our results reveal that endothelial cells are highly sensitive to inflammatory cytokines linked to ICI-M, showing a stronger response than cardiomyocytes, with distinct regulatory patterns depending on the cell type or patient group. As observed in humans, our preclinical model shows that few animals develop myocarditis, with only a subset exhibiting conduction abnormalities, myocardial lymphocytic infiltration, and upregulation of PD-L1 and GBP5 proteins, mirroring human observations. Conclusion This study integrates clinical, human cellular, and animal data, bridging the gap between fundamental research and patient care and reinforcing the relevance and validity of our results. By creating a continuum between clinical and fundamental research, this integrative and translational approach has led to significant breakthroughs in our understanding of ICI-M. It also aims to improve both the safety and efficacy of ICIs while paving the way for personalized management of ICI-M patients.