biostudies-literatureWei SCNIH Cancer CenterNIDDK NIH HHSNHLBI NIH HHSCancer Prevention and Research in TexasNCI NIH HHSthe Vanderbilt Mouse Metabolic Phenotyping CenterNIHNCI Cancer CenterNIH HHSNIGMS NIH HHS614-625https://www.ebi.ac.uk/biostudies/studies/S-EPMC8041233biostudies-literatureUnknown11(3)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 <i>Ctla4</i> in the context of complete genetic absence of <i>Pdcd1</i> 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 <i>Ctla4</i> and <i>Pdcd1</i> functionally interact in a gene dosage-dependent manner, providing a mechanism by which myocarditis ariseCancer discoveryA Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor-Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention.PMC80412335P30 CA68485–19T32 GM152284F30CA236157R01 HL155990U24 DK059637P30CA16672R35 HL144980F30 CA236157T32 GM007347R1203T32 GM0075692 U24 DK059637–16P30 CA016672S10 OD023475R01 HL141466R01 CA227481P30 CA068485R01CA227481U2C DK059637R56 141466T32GM007347R56 HL141466R01 141466Anang NASMeijers WCRao XWescott ECCourand PYWang JZhao YAxelrod MLKnollmann BCHimmel LELehmann LWhitley EAtolagbe OTMoslehi JJBalko JMEhrlich LIRWei SCSrinivasan JAllison JPSharma PMancuso JJJohnson DBLebrun-Vignes BLi YScreever EMWleklinski MJSalem JEfalseA Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor-Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention.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 <i>Ctla4</i> in the context of complete genetic absence of <i>Pdcd1</i> 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 <i>Ctla4</i> and <i>Pdcd1</i> functionally interact in a gene dosage-dependent manner, providing a mechanism by which myocarditis arise2021-01-01T00:00:00Z2021 Mar2026-05-02T11:36:49.091Z2022-02-11T10:06:14.126ZS-EPMC80412333325747010.1158/2159-8290.CD-20-085610.1158/2159-8290.cd-20-0856