Molecular predictors and mechanisms of immune checkpoint inhibitor-induced myocarditis: A case-control study with translational correlates.
Authors: Pang Steph A. , Flores Molina Manuel , Thébault Pamela , Zheng Yuming , Chou Hsiang , Goncalves Christophe , Wang Jingtao , Filimon Sabin Dragos , Nunes Filho Paulo Ricardo Santos , Capella Mariana Pilon , Esfahani Khashayar , Michel Caroline Maude , Ding Jun , Del Rincon Sonia Victoria , Hudson Marie , Lapointe Réjean , Miller Wilson H. 
Published: June 2024

12031

Background: Myocarditis from immune checkpoint inhibition (ICI) has been reported in 0.04-1.14% of patients on ICI, with mortality up to 50%. Self-antigens driving ICI-myocarditis are largely unknown. Shared T cell clones between heart and tumor have not yet been identified. We present the Montreal Immune-Related Adverse Events (MIRAE) myocarditis project, which seeks to elucidate cellular and molecular drivers of ICI-myocarditis. Methods: Our case-control study comprises 3 groups of patients on ICI: 1) ICI-myocarditis (per ASCO diagnostic criteria); 2) non-ICI troponemia (elevated troponins from non-immune etiology); and 3) controls matched by tumor type, sex, and age, with no troponemia. We analyzed blood from prior to ICI, at time of troponemia, or at 3-6 months after ICI initiation. Our multiomics pipeline spans cytokine profiling, immune cell subpopulation profiling of peripheral blood mononuclear cells (PBMCs) via single cell RNA and T/B cell receptor sequencing, spatial single-cell imaging proteomics, and spatial transcriptomics to localize sources of upregulated cytokines and to visualize cell-cell interactions. Results: Of 560 patients treated with ICI in our biobank, 4.3% had ICI-myocarditis. 19 myocarditis stored samples were included in our study. All 19 patients received steroids. Additional treatments were mycophenolate (32%), tofacitinib (21%), plasmapheresis (21%), IVIG (21%) and alemtuzumab (5%). 5 patients (26%) developed arrhythmias. 10 (47%) had concurrent irAE. There were no major cardiac adverse events nor deaths from myocarditis or other irAE. These encouraging results may reflect our hospital protocol of troponin screening during first 3 cycles of ICI, leading to earlier diagnosis and treatment. Elevations of blood neutrophil-to-lymphocyte ratio, alanine transaminase, and aspartate aminotransferase were associated with ICI-myocarditis. Plasma cytokine profiling of 13 ICI-myocarditis cases and controls revealed significant elevations of IP10, IL10, IL15 and IL13 at time of myocarditis. Subpopulation profiling of PBMCs is ongoing. Spatial phenotyping of an ICI-myocarditis biopsy demonstrated T cell and macrophage infiltration among cardiocytes and granulocyte accumulation within fibrotic tissue. Spatial transcriptomics analysis is ongoing for the ICI-myocarditis biopsy and 2 controls. Conclusions: This is one of the largest translational studies of ICI-myocarditis and controls. Our patients had improved clinical outcomes compared to those reported in the literature, which may be a result from our early screening. Our multiomics analyses of their biospecimens contributes novel data, such as spatial proteomics and transcriptomics analyses on heart tissue. Advancing our understanding of ICI-myocarditis will allow us to design screening strategies and more targeted treatments for ICI-myocarditis.