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Cited by 17Cancer Immunotherapy and BiomarkersViral Infections and Immunology ResearchCardiac Fibrosis and Remodeling

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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

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Racine, Jeremy J, Bachman, John F, Zhang, Ji-Gang, Misherghi, Adel, Khadour, Raheem, Kaisar, Sana, Bedard, Olivia, Jenkins, Catherine, Abbott, Annie, Forte, Elvira, Rainer, Peter, Rosenthal, Nadia, Sattler, Susanne, Serreze, David V·2024·The Journal of Immunology
DOI 10.4049/jimmunol.2300841PMC PMC10984778
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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.

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  • Following ICI therapy, 40% of patients with myocarditis experience concomitant myositis, confirmed in mouse models.

    “Following ICI therapy, 40% of patients with myocarditis experience concomitant myositis, confirmed in mouse models. 41,42,46,68,282”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [68]

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Metadata

Authors
Racine, J. J., Bachman, J. F., Zhang, J.-G., Misherghi, A., Khadour, R., Kaisar, S., Bedard, O., Jenkins, C., Abbott, A., Forte, E., Rainer, P., Rosenthal, N., Sattler, S., & Serreze, D. V.
Affiliations
  • Jackson Laboratory (US)
  • The Jackson Laboratory , Bar Harbor, ME
  • College of the Atlantic (US)
  • Imperial College London (GB)
  • Medical University of Graz (AT)
Corresponding author
  • Sattler, Susanne
  • Serreze, David V
ORCID
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2024-03-01
Volume
212
Issue
8
Pages
1287-1306
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
DOI
10.4049/jimmunol.2300841
PMC
PMC10984778
OpenAlex
W4392358875
Cited by
17
References
6
Citations by year
2026: 9 · 2025: 5 · 2024: 3
FWCI
2.91
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders
  • JDRF (3-PDF-2017-372-A-N)
  • Diabetes Research Connection (DRC 27 P20-0201 JR)
  • HHS | NIH | National Institute on Aging (T32AG062409)
  • HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DK095735)
  • HHS | NIH | NIH Office of the Director (U54OD020351, U54OD030187)
  • Mark Foundation For Cancer Research (MFCR ASPIRE Serreze FY22)
  • HHS | NIH | National Cancer Institute (P30CA034196)
  • HHS | NIH | National Institute of General Medical Sciences (P20GM103423)
  • Austrian Science Fund (P36588-B)
  • British Heart Foundation (P84083)
  • Fondation Leducq
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Infectious Diseases › Viral Infections and Immunology Research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
immune checkpoint inhibitor-associated myocarditis, anti-PD-1 therapy, immune-related adverse events, HLA-DQ8, myositis, CD4+ T cells, heart failure, mouse model, CRISPR/Cas9 genome editing
MeSH terms
Immune Checkpoint Inhibitors, Animals, Diabetes Mellitus, Experimental, HLA-DQ Antigens, Humans, Myocarditis, Myositis, Neoplasms, Mice, Inbred NOD, Mice

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