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A genetic mouse model recapitulates immune checkpoint inhibitor-associated myocarditis and supports a mechanism-based therapeutic intervention.

Abstract：

:Immune checkpoint inhibitors (ICI) targeting CTLA-4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events (irAEs), including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which mono-allelic 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 electrocardiographic abnormalities, closely recapitulating the clinical and pathological 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 CTLA-4-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.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

Wei SC,Meijers WC,Axelrod ML,Anang NAS,Screever EM,Wescott EC,Johnson DB,Whitley E,Lehmann L,Courand PY,Mancuso JJ,Himmel LE,Lebrun-Vignes B,Wleklinski MJ,Knollmann BC,Srinivasan J,Li Y,Atolagbe OT,Rao X,Zhao Y,Wa

doi

10.1158/2159-8290.CD-20-0856

subject

Has Abstract

pub_date

2020-11-30 00:00:00

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-20-0856

pub_type

杂志文章

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