Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy.

Document Type

Article

Publication Date

4-15-2024

Keywords

JMG, SS1, Humans, Mice, Animals, Myocarditis, Mice, Inbred NOD, Immune Checkpoint Inhibitors, Diabetes Mellitus, Experimental, Neoplasms, Myositis, HLA-DQ Antigens

JAX Source

J Immunol. 2024;212(8):1287-306.

ISSN

1550-6606

PMID

38426910

DOI

https://doi.org/10.4049/jimmunol.2300841

Grant

This work was supported in parts by JDRF Fellowship 3-PDF-2017-372-A-N and Diabetes Research Connection Grant 27 P20-0201 JR (to J.J.R.). J.F.B. received support from National Institute on Aging Grant T32AG062409. D.V.S. was supported by Division of Diabetes, Endocrinology, and Metabolic Diseases Grant DK095735 and NIH Office of the Director Grant U54OD020351. A.M. and R.K. were supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant P20GM103423 (via Maine IDeA Network of Biomedical Research Excellence). S.S. was supported by the Austrian Science Fund Grant P36588-B, British Heart Foundation Grant P84083, and by a grant from the Leducq Foundation. The bulk of this work was supported in part by Mark Foundation for Cancer Research Grant MFCR ASPIRE Serreze FY22 and National Cancer Institute Award P30CA034196. This work was also supported by NIH Office of the Director Grant U54OD030187

Abstract

Myocarditis has emerged as an immune-related adverse event of immune checkpoint inhibitor (ICI) cancer therapy associated with significant mortality. To ensure patients continue to safely benefit from life-saving cancer therapy, an understanding of fundamental immunological phenomena underlying ICI myocarditis is essential. We recently developed the NOD-cMHCI/II-/-.DQ8 mouse model that spontaneously develops myocarditis with lower mortality than observed in previous HLA-DQ8 NOD mouse strains. Our strain was rendered murine MHC class I and II deficient using CRISPR/Cas9 technology, making it a genetically clean platform for dissecting CD4+ T cell-mediated myocarditis in the absence of classically selected CD8+ T cells. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, anti-PD-1 administration accelerates skeletal muscle myositis. Using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses, we performed a thorough characterization of cardiac and skeletal muscle T cells, identifying shared and unique characteristics of both populations. Taken together, this report details a mouse model with features of a rare, but highly lethal clinical presentation of overlapping myocarditis and myositis following ICI therapy. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies.

Link to Full Text

Share

COinS