A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor–Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention
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Abstract
Abstract Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events, including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which monoallelic loss of Ctla4 in the context of complete genetic absence of Pdcd1 leads to premature death in approximately half of mice. Premature death results from myocardial infiltration by T cells and macrophages and severe ECG abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients. Using this model, we show that Ctla4 and Pdcd1 functionally interact in a gene dosage–dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4–Ig (abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis. Significance: We provide a preclinical model of ICI-associated myocarditis which recapitulates this clinical syndrome. Using this model, we demonstrate that CTLA4 and PD-1 (ICI targets) functionally interact for myocarditis development and that intervention with CTLA4–Ig (abatacept) attenuates myocarditis, providing mechanistic rationale and preclinical support for therapeutic clinical studies. See related commentary by Young and Bluestone, p. 537. This article is highlighted in the In This Issue feature, p. 521
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Abatacept alone or in combination with ruxolitinib has demonstrated clinical benefits in treating patients with ICI myocarditis and murine models.
“Additionally, as previously discussed, abatacept alone or in combination with ruxolitinib has demonstrated clinical benefits in treating patients with ICI myocarditis and murine models (Figure 2). 51,254,260”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [51]
The Results report that abatacept reduced mortality in the mouse model and ameliorated myocarditis in two additional patients; the Discussion describes the patient evidence as preliminary. The paper does not report treatment with abatacept combined with ruxolitinib, so it does not support that part of the claim. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPreclinical and clinical studies demonstrate that females exhibit a higher frequency and severity of ICI myocarditis, primarily driven by α-MyHC-specific autoreactive T cells.
“This hypothesis is further supported by preclinical and clinical studies demonstrating that females exhibit a higher frequency and severity of ICI myocarditis, primarily driven by α -MyHC-specific autoreactive T cells. 51,273,274”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [51]
The Results section ('Lethal haploinsufficiency of Ctla4 in the genetic absence of Pdcd1'; page unavailable) reports higher mortality in female than male model mice, and the Discussion describes emerging patient data associating female sex with increased myocarditis risk. The paper does not establish greater myocarditis severity in females or identify α-MyHC-specific autoreactive T cells as its primary driver; its Discussion treats the relevant antigens and mechanisms as unresolved. (LLM, conf=0.89)
Experimental — accuracy not yet measuredIn this model, clonal and activated CD8+ T lymphocytes are necessary for the development of myocarditis, and autoreactive α-MyHC-specific T cells are a crucial mediator of disease pathogenesis.
“clonal and activated CD8 + T lymphocytes are necessary for the development of myocarditis, with further investigation identifying autoreactive α -MyHC-specific T cells as a crucial mediator of disease pathogenesis”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [51]
The Results section (‘Myocarditis manifests due to Ctla4 haploinsufficiency in the absence of Pdcd1’; page unavailable) reports abundant CD8+ T-cell infiltration in affected hearts, and the Discussion links the model to aberrant T-cell activation. Our copy does not establish that CD8+ cells are clonal or necessary for myocarditis, or identify α-MyHC-specific T cells as crucial mediators. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRecent studies implemented pathogenic T cells as potential diagnostic or therapeutic targets for autoimmune myocarditis including ICI myocarditis, demonstrating promising outcomes at both clinical and preclinical levels.
“Recent studies implemented pathogenic T cells as potential diagnostic or therapeutic targets for autoimmune myocarditis including ICI myocarditis, demonstrating promising outcomes at both clinical and preclinical levels. 51,64,238,254,260,311,312”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [51]
A genetic mutant mouse model for ICI myocarditis with haploinsufficiency of CTLA-4 in a PD-1 knockout C57BL/6 background developed spontaneous myocarditis with a 50% fatality rate within 3 months.
“These mice developed spontaneous myocarditis with a 50% fatality rate within 3 months.”
From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [51]
A murine model of myocarditis provided a rationale for using CTLA4-Ig (abatacept) to block T-cell costimulation.
“For example, the recent development of a murine model of myocarditis, one of the most feared complications of ICT, provided a rationale for the use of CTLA4-Ig (abatacept), which blocks T-cell costimulation, although an open question remains as to whether this will interfere with antitumor immunity (97,98).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [97]
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References 41 · Cited by 290
Research works printed but not linked: 1
- [13]Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016; 375: 1749– 55. 27806233 PMC5247797
- Authors
- Wei, S. C., Meijers, W. C., Axelrod, M. L., Anang, N.-A. A. S., Screever, E. M., Wescott, E. C., Johnson, D. B., Whitley, E., Lehmann, L., Courand, P.-Y., Mancuso, J. J., Himmel, L. E., Lebrun-Vignes, B., Wleklinski, M. J., Knollmann, B. C., Srinivasan, J., Li, Y., Atolagbe, O. T., Rao, X., Zhao, Y., Wang, J., Ehrlich, L. I. R., Sharma, P., Salem, J.-E., Balko, J. M., Moslehi, J. J., & Allison, J. P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Vanderbilt University Medical Center (US)
- University Hospital Heidelberg (DE)
- Inserm (FR)
- 7Department of Pharmacology, APHP. Sorbonne Université, INSERM, CIC-1901, UNICO-GRECO Cardiooncology Program, Paris, France.
- 2Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
- The University of Texas at Austin (US)
- ORCID
- Wei, Spencer C.
- Meijers, Wouter C.
- Axelrod, Margaret L.
- Anang, Nana-Ama A.S.
- Screever, Elles M.
- Wescott, Elizabeth C.
- Johnson, Douglas B.
- Whitley, Elizabeth
- Lehmann, Lorenz
- Courand, Pierre-Yves
- Mancuso, James J.
- Himmel, Lauren E.
- Wleklinski, Matthew J.
- Srinivasan, Jayashree
- Li, Yu
- Atolagbe, Oluwatomisin T.
- Rao, Xiayu
- Zhao, Yang
- Wang, Jing
- Ehrlich, Lauren I.R.
- Sharma, Padmanee
- Salem, Joe-Elie
- Balko, Justin M.
- Moslehi, Javid J.
- Allison, James P.
- Venue
- Cancer Discovery
- Published
- 2021-03-01
- Volume
- 11
- Issue
- 3
- Pages
- 614-625
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC8041233
- OpenAlex
- W3108805504
- Cited by
- 290
- References
- 41
- Citations by year
- 2026: 51 · 2025: 40 · 2024: 60 · 2023: 54 · 2022: 53 · 2021: 31
- FWCI
- 12.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Cancer Prevention and Research in Texas (R1203)
- NCI Cancer Center (P30CA16672)
- NIH Cancer Center (5P30 CA68485–19)
- the Vanderbilt Mouse Metabolic Phenotyping Center (2 U24 DK059637–16)
- NIH (R56 141466, R01 141466, R01CA227481, T32GM007347, F30CA236157)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- immune checkpoint inhibitor-associated myocarditis, CTLA-4, PD-1, PDCD1, abatacept, immune-related adverse events, T cell infiltration, macrophage infiltration, electrocardiographic abnormalities, premature mortality, mouse model, combination immunotherapy
- MeSH terms
- Immune Checkpoint Inhibitors, Animals, Disease Models, Animal, Disease Susceptibility, Electrocardiography, Humans, Myocarditis, Neoplasms, Biomarkers, Tumor, Disease Management, Mice, Molecular Targeted Therapy, Cardiotoxicity
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