Abstract P4-06-30: Adipose PD-L1 modulates checkpoint blockade immunotherapy efficacy in breast cancer

Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) play important roles in modulating antitumor immune response and are targeted by checkpoint blockade immunotherapy. While PD-L1 expression in both tumor and host cells is associated with antitumor therapeutic efficacy, the exact contribution of PD-L1 in various tissue and cell compartments to antitumor immune response remains to be elucidated. Here we show that PD-L1 expression is markedly elevated in human and mouse mature adipocytes compared to their preadipocyte counterparts. When co-cultured with mouse splenocytes in vitro, adipocytes prevent anti-PD-L1 antibody from activating CD8+T cells. Genetic ablation of adipose PD-L1 obliterates the inhibitory effect of adipocytes on anti-PD-L1 antibody. Conversely, enforced PD-L1 expression in preadipocytes confers the antibody-inhibitory activity. GW9662, a pharmacologic inhibitor of peroxisome proliferator-activated receptor γ (PPARγ) in adipogenesis, selectively reduces PD-L1 expression in mouse adipose tissue. The same PPARγ antagonist also enhances the antitumor efficacy of checkpoint blockade antibodies for treating multiple mammary tumors. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression. Citation Format: Wu B, Sun X, Gupta HB, Yuan B, Ge F, Li J, Hu Y, Curiel TJ, Li R. Adipose PD-L1 modulates checkpoint blockade immunotherapy efficacy in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-30.