Targeting ligand PDL1 for cardiotoxicity assessment and cardiac protection in immune-related myocarditis.

Abstract

AIMS: The role of cardiac programmed cell death ligand 1 (PDL1) in immune checkpoint inhibitor (ICI) - related myocarditis (irMyocarditis) remains unclear. We aimed to investigate whether ligand PDL1 could serve as an early indicator and a potential therapeutic target for irMyocarditis. METHODS: Cardiac PDL1 expression was assessed using single-nucleus RNA sequencing and multiplex immunohistochemistry in human patients and mouse models of irMyocarditis. A PDL1-targeted magnetic resonance imaging (MRI) nanoprobe was developed for noninvasive imaging of irMyocarditis. Additionally, an adeno-associated virus 9 (AAV9) vector was employed to deliver the PDL1 gene to cardiomyocytes, and its therapeutic effects on irMyocarditis were evaluated in a mouse model. RESULTS: PDL1 expression was significantly elevated in the myocardium of irMyocarditis patients and mouse models. The PDL1-targeted MRI nanoprobe successfully detected myocarditis in vivo, with enhanced cardiac signals observed in affected mice compared to isotype controls. Therapeutic intervention using AAV9-mediated PDL1 gene delivery significantly reduced immune cell infiltration and cardiomyocyte apoptosis, improving left ventricular ejection fraction over a 2-month follow-up period. CONCLUSIONS: This study identifies PDL1 as a critical biomarker and therapeutic target for irMyocarditis. PDL1-targeted MRI nanoprobe enables early, noninvasive diagnosis, while AAV9-mediated PDL1 gene therapy offers a promising strategy to mitigate irMyocarditis and restore cardiac function in ICI therapy recipients.