Adipocyte PD-L1 suppresses anti-tumor immune response and promotes breast cancer progression

PD-L1 has become a major target in anti-cancer immunotherapy, however the overall response rate still remains relatively low among most types of cancers, notably breast cancer. There is an unmet need to boost efficacy of immune checkpoint blockade therapies. While both tumor and host immune cell-derived PD-L1 are implicated in immune suppressive functions of PD-L1, the exact immunosuppressive contribution of PD-L1 from different host tissues is little studied. Here we show that PD-L1 expression is significantly higher in human breast adipose tissue versus stromal vascular fractions. In vitro adipogenesis of mouse pre-adipocytes significantly up-regulates PD-L1 versus pre-adipocytes. In vitro co-culture shows that adipocyte PD-L1 suppresses T cell activation and response to anti-PD-L1. In an adipocyte-specific knockout (KO) mouse model, we show that syngeneic mammary tumors grow slower in KO than wildtype hosts. Immunophenotyping shows that tumors grown in KO mice have higher CD8+and CD4+ T cell infiltration as well as more CD8+ Prf+ cytotoxic T cells. Tumor tissue RNA-seq analysis reveals that genetic ablation of adipocyte PD-L1 confers a distinct transcriptomic signature of T cell activation and tumor killing. Our current findings uncover a previously unappreciated source of immune suppressive PD-L1 in the breast cancer microenvironment and could inform novel therapeutic strategies through targeting tumor-surrounding adipose tissue for treating breast cancer.