Adipocyte PD-L1 Modulates Checkpoint Blockade Cancer Immunotherapy Efficacy

PD-L1 expression in both tumor and host cells correlates with antitumor therapeutic efficacy, but the specific contribution of PD-L1 in various cell compartments to antitumor immunity remains to be fully elucidated. Here we show that PD-L1 expression is significantly elevated in human and mouse mature adipocytes versus preadipocytes. When co-cultured with mouse splenocytes, adipocytes reduce αPD-L1 antibody-mediated CD8+ T cell activation. Genetic ablation of adipose PD-L1 obliterates, while enforced PD-L1 expression in preadipocytes confers, the immune-inhibitory effect of adipocytes. Pharmacologic inhibition of adipogenesis by the PPAR gamma antagonist GW9662 reduces adipose PD-L1 expression and enhances the antitumor efficacy of αPD-L1 and αPD-1 immunotherapies in female mice bearing syngeneic melanoma or mammary tumors. Combo treatment with GW9662 and αPD-L1 increased antitumor lymphocytes infiltration versus control or single agent treatment. In diet-induced obese female mice, combo treatment elicited suppressed melanoma growth, although less effectively versus lean females. In contrast to females, melanomas in either lean or obese male mice exhibited no applicable response to combo treatment. More strikingly, obese males lost αPD-L1 single treatment response versus lean males, with lower CD45+ and CD3+ T cell infiltration in tumors. However, castration in lean males rescued efficacy of combo treatment. These data suggest an antagonistic effect of male hormones in this combination. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy. The potential impact of sex and obesity warrants consideration in future development of immunotherapy-related combination therapy.