Myeloid specific PD-L1 deletion promotes cardiac dysfunction and myocardial inflammation 2162

Abstract Description PD-L1 inhibitors are effective in cancer treatment but can cause fatal heart issues. Despite the significant impact of these adverse events, there is limited research underlying mechanisms of immune checkpoint inhibitor-mediated cardiotoxicities. PD-L1 exhibits high expression levels over cardiac myeloid cells. However, the precise role of myeloid-specific PD-L1 (myeloid-PD-L1) signaling in mediating autoimmune cardiac disease pathology remains unclear. To study the role of myeloid-PD-L1 in cardiac pathophysiology, we generated myeloid-PD-L1 KO mice. Interestingly, as early as 1.5 months of age, myeloid-PD-L1-KOs displayed marked cardiac dysfunction as reflected by reduced LVEF, LVFS, and HF markers. Immune profiling was conducted whether chronic inflammation contributes to cardiac dysfunction and remodeling. KO hearts demonstrated excessive systemic inflammation, substantial immune infiltration, and activation. Thus, a pro-inflammatory cytokine storm was also detected in the KO hearts. Furthermore, myeloid-PD-L1 KO hearts showed increased pro-inflammatory CCR2+ monocytes and macrophage recruitment. Our data with myeloid-PD-L1 KOs suggest that deleting PD-L1 in myeloid lineage promotes myocardial and systemic inflammation through immune cell activation and recruitment of CCR2+ MΦs. Subsequently, this leads to impaired cardiac pathophysiology. These translational studies will directly evaluate the potential of targeting myeloid-PD-L1 signaling to alleviate cardiac damage. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)