Adipocyte PD-L1 in the Breast Tumor Microenvironment

ABSTRACT Programmed death-ligand 1 (PD-L1) and its receptor, programmed cell death protein 1 (PD-1), modulate anti-tumor immunity and are major targets of current checkpoint blockade immunotherapies. However, clinical trials of αPD-L1/αPD-1 antibodies in breast cancer to date have demonstrated only limited efficacy. The importance of a breast-specific tumor microenvironment (TME) in regulating anti-tumor immunity is vastly under- explored. Given the abundance of adipocytes in breast tissue, the well-documented association between adiposity and breast cancer-related mortality, and the emerging obesity paradox in anticancer immunotherapy, it is imperative to investigate the molecular underpinnings of the complex adipose-immune-tumor network within the adipocyte-rich breast TME. We recently identified a previously unappreciated, functionally significant source of PD-L1 in white adipocytes. Adipocyte PD-L1 is markedly induced during adipogenesis and obesity-related chronic inflammation. Using an adipocyte-specific knockout mouse model, we demonstrate an important role of adipocyte PD-L1 in promotion of tumor growth and attenuation of anti-tumor immunity. Furthermore, our preliminary data indicate physical and functional interactions between PD-L1 and lipid metabolism-related proteins and pathways in adipocytes, which suggests an adipocyte-intrinsic function of PD-L1. Based on our preliminary data, we hypothesize that adipocyte PD-L1 impedes anti-tumor lymphocytes and/or abets tumor cells through a lipid metabolism-related mechanism. We further propose that this action of adipocyte PD-L1 is particularly important at the tumor margin of immune-excluded tumors, where adipocytes are in proximity with both tumor and immune cells. We will combine our established tools and expertise in cancer biology, tumor immunology, and transcriptional regulation to validate this novel hypothesis through the following Aims: (1) Delineate how adipocyte PD-L1 mediates adipose-immune-tumor crosstalk, (2) Determine how adipocyte PD-L1 expression is regulated, and (3) Determine how adipocyte PD-L1 impacts immunotherapy in obese vs non-obese hosts. Our studies on adipocyte PD-L1 signaling in lipid metabolism will provide new molecular explanations for PD-L1 action in tumor immunology, a clear departure from the prevailing paradigm regarding tumor/immune PD-L1 actions. This proposed work represents a conceptual advance toward understanding the spatial landscape of the breast TME in immune regulation and tumorigenesis – a clinically relevant yet mechanistically under-explored problem. Our results could lay a solid foundation for developing new tools that predict and enhance therapeutic response to aPD-1/aPD-L1 immunotherapy for breast cancer patients, especially those with obesity.