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

Award Number: R01HL176552
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $425,505 )
2025	2025	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cardiovascular Diseases Research	000	1	9/15/2025	NEW	$425,505
														Subtotal = $425,505

Grand Total All Awards = $425,505

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

Award Number: R01HL176552

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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