T cells specific for α-myosin drive immunotherapy-related myocarditis

Abstract

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to immune checkpoint inhibitor (ICI) utility in anti-cancer therapy1. The pathogenesis of ICI-myocarditis is poorly understood. Pdcd1-/-Ctla4+/-mice recapitulate clinicopathologic features of ICI-myocarditis, including myocardial T cell in ltration2. Single cell RNA/T cell receptor (TCR) sequencing on the cardiac immune in ltrate of Pdcd1-/-Ctla4+/-mice identi ed activated, clonal CD8+ T cells as the dominant cell population. Treatment with anti-CD8, but not anti-CD4, depleting antibodies rescued survival of Pdcd1-/-Ctla4+/-mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients which required CD8+ T cells. Alpha-myosin, a cardiac speci c protein absent from the thymus3,4, was identi ed as the cognate antigen source for three MHC-I restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from two patients with ICI-myocarditis were expanded by alpha-myosin peptides, and these alpha-myosin expanded T cells shared TCR clonotypes with diseased heart and skeletal muscles, indicating that alpha-myosin may be a clinically important autoantigen in ICI-myocarditis. These studies underscore the critical role for cytotoxic CD8+ T cells, are the rst to identify a candidate autoantigen in ICI-myocarditis and yield new insights into ICI toxicity pathogenesis.Grant 5P30 CA68485-19 and the Shared Instrumentation Grant S10 OD023475-01A1 for the Leica Bond RX. The Vanderbilt VANTAGE Core, including A. Jones and L. Raju, provided technical assistance for this work. VANTAGE is supported in part by a CTSA Grant (5UL1 RR024975-03), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126) and the NIH/NCRR (G20 RR030956). Figures 1a and 4b were created with BioRender.com.Con ict Interest Disclosure M.L. Axelrod is listed as a coinventor on a provisional patent application for methods to predict therapeutic outcomes using blood-based gene expression patterns, that is owned by Vanderbilt University Medical Center, and is currently unlicensed. S.C. Wei is an employee of Spotlight Therapeutics, a consultant for BioEntre, and an inventor on a patent for a genetic mouse model of autoimmune adverse events and immune checkpoint blockade therapy (PCT/US2019/050551) pending to Board of Regents, The University of Texas System. J.C. Rathmell is a founder, scienti c advisory board member, and stockholder of Sitryx Therapeutics, a scienti c advisory board member and stockholder of Caribou Biosciences, a member of the scienti c advisory board of Nirogy Therapeutics, has consulted for Merck, P zer, and Mitobridge within the past three years, and has received research support from Incyte Corp., Calithera Biosciences, and Tempest Therapeutics. P.B. Ferrell receives research support from Incyte Corporation. D.B.Johnson has served on advisory boards or as a consultant for BMS, Catalyst

The year in cardiovascular medicine 2022: the top 10 papers in cardio-oncology

“…Since the first description of cases with fulminant immune checkpoint inhibitor (ICI) myocarditis in 2016, there has been a vivid interest in identifying the culprit process, if not the nature and molecular target of T cells felt to have gone rogue. In a genetic mouse model with homozygous knockout of Pdcd1 and heterozygous deletion of Ctla4 , Axelrod et al 6 identified highly activated and clonally expanded CD8 T cells as the dominant immune population and depletion of CD8 T cells but not CD4 T cells nearly completely prevented the 50 mortality rate otherwise seen. In a candidate auto-antigen approach, alpha-myosin was identified as one leading target, noted also in three patients with ICI myocarditis.…”

Clonally-Expanded, Thyrotoxic Autoimmune Mediator CD8+T cells Driven by IL21 Contribute to Checkpoint Inhibitor Thyroiditis

“…Ongoing studies are interrogating these TCR sequences of clonally expanded CD8 + autoimmune mediators to determine antigen targets in thyroid IRAE. Clonal expansion of T cells has been linked to IRAE risk in two recent studies (22, 45) , including clonal expansion of CD8 + T cells in a mouse model of ICI-associated myocarditis (45) . Importantly, whether clonal expansion also occurs in human ICI-associated myocarditis is unknown as this study did not evaluate immune infiltrates in the tissues of ICI-myocarditis patients.…”

The Role of Single-Cell Profiling and Deep Immunophenotyping in Understanding Immune Therapy Cardiotoxicity

“…In a recently published manuscript, scRNA-seq or TCR sequencing performed on Pdcd1 −/− Ctla4 +/− mice showed expansion of activated, clonal CD8 + T cells, with alpha-myosin found as an autoantigen. 11 These findings suggest promising therapeutic targets to treat cardiac IRAEs.…”