PD-L1 antibody-induced cardiac dysfunction is regulated by CCR5-positive macrophages.

Abstract

The programmed death-ligand 1 (PD-L1) antibody, while revolutionizing oncology through immune checkpoint blockade, is increasingly associated with clinically significant cardiac immune-related adverse events (irAEs). This study systematically investigates the early cardiotoxic effects of PD-L1 inhibition using murine models, revealing through integrated cardiac functional assessments (systolic performance, myocardial deformation, and electromechanical synchronicity) and spatial transcriptomics that PD-L1 antibody treatment acutely disrupts cardiac synchronicity and contractile function. Mechanistic profiling identified monocyte-derived C-C motif chemokine receptor 5-positive (CCR5+) macrophage proliferation driven by PD-L1-induced C-C motif chemokine ligand 5 (CCL5) chemokine signaling, with flow cytometry/immunofluorescence confirming CD45+CD11b+F4/80+CCR5+ macrophage infiltration in treated myocardium. Therapeutic intervention with the CCR5 antagonist maraviroc demonstrated multi-modal cardiac protection: attenuating cardiac dysfunction, reducing CCR5+ macrophage recruitment, suppressing CCL5 overproduction, and modulating redox/apoptosis pathways through hypoxia-inducible factor 1α (HIF-1α)/pyruvate kinase isozyme type M2 (PKM2) Y105 phosphorylation regulation and apoptosis inhibition. Notably, although maraviroc failed to potentiate the anti-tumor effect of PD-L1 therapy, it effectively attenuated the PD-L1-associated myocardial toxicity without diminishing the anti-tumor response in melanoma-bearing mice. These findings delineate a CCL5/CCR5 axis as the central mechanism underlying early PD-L1-induced cardiotoxicity, while establishing CCR5 blockade as a translatable strategy for preventing immunotherapy-associated cardiac complications, with maraviroc demonstrating pleiotropic protective effects spanning immune modulation, metabolic reprogramming, and apoptosis control.