PPARγ inhibition boosts efficacy of PD-L1 Checkpoint Blockade Immunotherapy against Murine Melanoma in a sexually dimorphic manner

Immune checkpoint blockade-based immunotherapy has become standard of care for multiple cancer types. However, the overall response rates among various cancer types still remain unsatisfactory. There is a pressing clinical need to identify combination therapies to improve efficacy of anticancer immunotherapy. We previously showed that pharmacologic inhibition of PPARgamma by GW9662 boosts alphaPD-L1 and alphaPD-1 antibody efficacy in treating murine mammary tumors. In addition, we defined sexually dimorphic alphaPD-L1 efficacy in B16 melanoma. Here, we show a sexually dimorphic response to the combination of GW9662 and alphaPD-L1 immunotherapy in B16 melanoma. Combination effects were observed in female, but not male hosts. Neither female oophorectomy impairs, nor does male castration rescue the combination effects, suggesting a sex hormone-independent response to this combination therapy. In diet-induced obese females, melanoma growth remained responsive to the combination treatment, albeit less robustly than lean females. These findings are informative for future design and application of immunotherapy-related combination therapy for treating human melanoma patients by taking gender and obesity status into consideration.