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

• Published in: International journal of biological sciences Vol. 16; no. 9; pp. 1526 - 1535
• Main Authors: Wu, Bogang, Sun, Xiujie, Yuan, Bin, Ge, Fei, Gupta, Harshita B, Chiang, Huai-Chin, Li, Jingwei, Hu, Yanfen, Curiel, Tyler J, Li, Rong
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2020; Ivyspring International Publisher
• Subjects: Adipocytes; Antibodies; Anticancer properties; Cancer therapies; Castration; Cytokines; Diet; Females; Flow cytometry; Gender; Immune checkpoint; Immunotherapy; Lymphocytes; Males; Medical prognosis; Melanoma; Obesity; PD-L1 protein; Peroxisome proliferator-activated receptors; Research Paper; Sex hormones; Sexual dimorphism; Skin cancer; Survival analysis; Tumors; PD-L1; PPARγ; obesity; sexual dimorphism; Melanoma; immunotherapy
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.42966

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 PPARγ by GW9662 boosts αPD-L1 and αPD-1 antibody efficacy in treating murine mammary tumors. In addition, we defined sexually dimorphic αPD-L1 efficacy in B16 melanoma. Here, we show a sexually dimorphic response to the combination of GW9662 and αPD-L1 immunotherapy in B16 melanoma. Combination effects were observed in female, but not male hosts. Neither female oöphorectomy 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.