Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by enhancing the immune system’s ability to recognize and attack tumor cells. However, despite their efficacy, ICIs can trigger immune-related adverse events (jrAEs), including severe cardiotoxicities such as myocarditis, heart failure, and arrhythmias. While previous studies have primarily focused on T-cell-mediated mechanisms, the role of myeloid-specific PD-L1 signaling in ICI-induced myocarditis remains poorly understood. Methods and Results: In this study, we investigated the impact of myeloid-specific PD-L1 deletion using a Lyz2tm1 (Cre)Ifo mouse model. Surprisingly, as early as 1 month of age, myeloid-PD-L1 KOs displayed marked cardiac dysfunction as reflected by reduced LVEF, LVFS, and elevated HF markers. Immune profiling was conducted whether chronic inflammation contributes to cardiac dysfunction and remodeling. Interestingly, KO hearts demonstrated excessive systemic inflammation, substantial myocardial immune infiltration (innate and adaptive), and activation. Of note, the cardiac and systemic inflammation phenotype precedes the onset of cardiac dysfunction and adverse remodeling. This implies that excessive inflammation is critical to driving impaired cardiac pathophysiology. Notably, we observed increased recruitment of pro-inflammatory CCR2+ macrophages in KO hearts, suggesting a crucial role of myeloid PD-L1 in modulating immune response and cardiac pathology. Additionally, fibroblasts from wild-type mice co-cultured with bone marrow-derived macrophages (BMDMs) from KO mice exhibited significant upregulation of fibrosis-related genes and inflammatory cytokines. Furthermore, BMDMs from KO co-cultured with T-cells from wild-type mice lead to increased T-cell frequency and activation, as demonstrated by the upregulation of TCRαβ+, CD4+ and CD8+ T-cell populations, with a pro-inflammatory Th1 polarization. Conclusion: Overall, our findings demonstrate that myeloid-derived immunosuppressive PD-L1 signaling is essential to maintaining adult heart homeostasis. The absence of myeloid PD-L1 leads to progressive cardiac dysfunction and adverse remodeling, likely driven by excessive inflammation. Nonetheless, we also identified CCR2+ macrophages as a targetable population in myeloid-PD-L1-mediated myocarditis. Future studies should explore whether interventions targeting pathogenic CCR2+ macrophages could be leveraged to halt or reverse ICI-induced cardiac dysfunction.
Cora et al. (Fri,) studied this question.