PD-1/PD-L1 inhibitors induce myocarditis by recruiting circulating CCL5+CD8+ T cells to the heart, where they interact with CCR5+ macrophages to activate fibroblasts.
Does PD-1/PD-L1 inhibitor treatment alter the immunological network and cellular composition in the heart and PBMC of mice?
Single-cell RNA sequencing reveals that the CCL5/CCR5 axis and circulating CCL5+CD8+ T cells mediate immune checkpoint inhibitor-induced myocarditis, highlighting potential therapeutic and diagnostic targets.
Absolute Event Rate: 0% vs 0%
Abstract Immune checkpoint inhibitors (ICIs) targeted PD-1/PD-L1 axis generate immune-related adverse events such as myocarditis, limiting their clinical application. Herein, we tried to explore the potential mechanism of ICIs-induced myocarditis. We performed single-cell RNA sequencing of heart tissues and peripheral blood mononuclear cells (PBMC) collected from mice with or without a relative low dose of PD-1/PD-L1 inhibitor (BMS-1) treatment. Compared with PBS treatment, BMS-1 treatment increased T, B, NK cells, and neutrophils but decreased macrophages in the heart. Four T cell subclusters in the heart were identified, including Treg, LEF1+CD4+ T, CCL5+CD8+ T, and STMN1+CD8+ T cells. The BMS-1-heart exhibited increased CCL5+CD8+ T cells depicted by elevated Nkg7 and Ccl5 gene expression compared with the PBS-heart. The number of macrophages declined but revealed inflammatory activity in the BMS-1-heart. Interestingly, CCR5, a receptor for CCL5 expressed in both CCR2− resident and CCR2+ recruit macrophages in the heart, was upregulated by the BMS-1 treatment. In addition, fibroblasts, not endothelial cells, showed an inflammatory activation state. Last, we identified increased CCL5+CD8+ T cells in the BMS-1-PBMC. Immunofluorescence staining also confirmed significantly elevated CCL5+CD8+ T cells in the BMS-1-heart than that of PBS-heart. BMS-1 seems to recruit circulating CCL5+CD8+ T cells to the heart, which further interact with CCR5+ macrophages, resulting in fibroblast activation. The CCL5/CCR5 axis and circulating CCL5+CD8+ T cells may be potential therapeutic/diagnostic strategies for ICIs-induced myocarditis.
Yan et al. (Thu,) reported a other. PD-1/PD-L1 inhibitors induce myocarditis by recruiting circulating CCL5+CD8+ T cells to the heart, where they interact with CCR5+ macrophages to activate fibroblasts.