Molecular Pathways and Cellular Subsets Associated with Adverse Clinical Outcomes in Overlapping Immune-Related Myocarditis and Myositis

Authors

Bilal A Siddiqui
Nicolas L Palaskas
Sreyashi Basu
Yibo Dai
Zhong He
Shalini S Yadav
James P Allison
Rahul A Sheth
Sudhakar Tummala
Maximilian Buja
Meenakshi B Bhattacharjee
Cezar Iliescu
Anishia Rawther-Karedath
Anita Deswal
Linghua Wang
Padmanee Sharma
Sumit K Subudhi

Publication Date

8-1-2024

Journal

Cancer Immunology Research

DOI

10.1158/2326-6066.CIR-24-0011

PMID

38768394

PMCID

PMC12302522

PubMedCentral® Posted Date

7-28-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Immune checkpoint therapies (ICT) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we performed single-cell RNA sequencing of heart and skeletal muscle biopsies obtained from living patients with cancers treated with ICTs and admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n = 10; myocarditis-only, n = 1) or ICT-exposed patients ruled out for toxicity utilized as controls (n = 9). All biopsies were obtained within 96 hours of clinical presentation. Analyses of 58,523 cells revealed CD8+ T cells with a cytotoxic phenotype expressing activation/exhaustion markers in both myocarditis and myositis. Furthermore, the analyses identified a population of myeloid cells expressing tissue-resident signatures and FcγRIIIa (CD16a), which is known to bind IgG and regulate complement activation. Immunohistochemistry of affected cardiac and skeletal muscle tissues revealed protein expression of pan-IgG and complement product C4d, which were associated with the presence of high-titer serum autoantibodies against muscle antigens in a subset of patients. We further identified a population of inflammatory IL1B+TNF+ myeloid cells specifically enriched in myocarditis and associated with greater toxicity severity and poorer clinical outcomes. These results provide insight into the myeloid subsets present in human immune-related myocarditis and myositis tissues and nominate new targets for investigation into rational treatments to overcome these high-mortality toxicities. See related Spotlight by Fankhauser et al., p. 954.

Keywords

Humans, Myocarditis, Myositis, Male, Female, Middle Aged, Immune Checkpoint Inhibitors, Aged, Neoplasms, CD8-Positive T-Lymphocytes, Adult, Receptors, IgG, Muscle, Skeletal, Single-Cell Analysis

Published Open-Access

yes

Recommended Citation

Siddiqui, Bilal A; Palaskas, Nicolas L; Basu, Sreyashi; et al., "Molecular Pathways and Cellular Subsets Associated with Adverse Clinical Outcomes in Overlapping Immune-Related Myocarditis and Myositis" (2024). Faculty, Staff and Student Publications. 4997.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4997