The Role of Cell-Specific PD-L1 in cardiac pathophysiology post Ischemic Injury and Cancer

Project Summary Immunotherapy, particularly immune checkpoint inhibitors (ICI), is a rapidly advancing cancer treatment. Despite its high effectiveness, ICI pose the risk of immune-related adverse events (IRAEs), including potentially fatal cardiotoxicities. Limited research into the underlying mechanisms of ICI-mediated cardiotoxicities emphasizes the need for further investigation. Monoclonal antibodies targeting immune checkpoint inhibitors like programmed death-1(PD-1), programmed death-ligand-1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) have gained prominence in cancer treatment. PD-L1 is abundantly expressed in cardiac tissue across major cell types including fibroblasts (FB) and myeloid cells. FB activation, fibrosis, and inflammation are central to ischemic cardiac injury, repair, and remodeling. Cross-talk between fibroblasts and immune cells is crucial for healing and remodeling the ischemic heart. Indeed, significant upregulation of PD-L1 was observed in fibroblasts (FBs) and myeloid cells within the ischemic hearts during heart injury. Employing fibroblast-specific PD-L1 KOs, our preliminary data indicate FB-PD-L1's role in driving cardiac inflammation and adverse remodeling post-MI. Pilot data on myeloid cell-specific PD-L1 KOs suggest that deleting PD-L1 in myeloid lineage promotes myocardial inflammation and leads to cardiac dysfunction and adverse remodeling. The preliminary data strongly support our overall hypothesis that FB-PD-L1 / Myeloid-PD-L1 is a critical regulator of the repair and remodeling of the infarcted heart. However, the specific role of each cell type in the PD-L1 signaling axis-mediated autoimmune cardiac disease pathology remains unclear. Furthermore, our preliminary results demonstrate that myeloid-PD- L1 may regulate the repair and remodeling of the ischemic heart by regulating the recruitment of pro-inflammatory CCR2+ macrophages and promoting Th17 cell polarization. Our studies will specifically aim to unravel the detailed mechanisms underlying cardiotoxicity and tumor efficacy mediated by fibroblast (FB) and myeloid- specific PD-L1 in syngeneic colorectal cancer models (MC38). Recognizing the dual roles of CCR2+ macrophages and Th17 in both promoting tumorigenesis and contributing to cardiac remodeling, we also propose interventions targeting CCR2+ macrophages and Th17 cells to preserve cardiac pathophysiology while maintaining antitumor efficacy during PD-L1 inhibition in myeloid cells. Thus the development of innovative strategies to mitigate cardiotoxicity induced by cancer therapeutics holds substantial promise for public health.