Int J Biol Sci 2020; 16(9):1526-1535. doi:10.7150/ijbs.42966 This issue

Research Paper

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

Bogang Wu1, Xiujie Sun1, Bin Yuan1, Fei Ge2, Harshita B. Gupta3, Huai-Chin Chiang1, Jingwei Li2, Yanfen Hu1, Tyler J. Curiel3✉, Rong Li1✉

1. Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC 20037, USA.
2. Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
3. Department of Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Wu B, Sun X, Yuan B, Ge F, Gupta HB, Chiang HC, Li J, Hu Y, Curiel TJ, Li R. PPARγ inhibition boosts efficacy of PD-L1 Checkpoint Blockade Immunotherapy against Murine Melanoma in a sexually dimorphic manner. Int J Biol Sci 2020; 16(9):1526-1535. doi:10.7150/ijbs.42966. Available from https://www.ijbs.com/v16p1526.htm

File import instruction

Abstract

Graphic abstract

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.

Keywords: Melanoma, immunotherapy, PD-L1, PPARγ, obesity, sexual dimorphism