Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

Authors

Bogang Wu, University of Texas Health Science Center at San Antonio
Xiujie Sun, University of Texas Health Science Center at San Antonio
Harshita B. Gupta, University of Texas Health Science Center at San Antonio
Bin Yuan, University of Texas Health Science Center at San Antonio
Jingwei Li, University of Texas Health Science Center at San Antonio
Fei Ge, University of Texas Health Science Center at San Antonio
Huai Chin Chiang, University of Texas Health Science Center at San Antonio
Xiaowen Zhang, University of Texas Health Science Center at San Antonio
Chi Zhang, University of Texas Health Science Center at San Antonio
Deyi Zhang, University of Texas Health Science Center at San Antonio
Jing Yang, University of Texas Health Science Center at San Antonio
Yanfen Hu, University of Texas Health Science Center at San Antonio
Tyler J. Curiel, University of Texas Health Science Center at San Antonio
Rong Li, University of Texas Health Science Center at San Antonio

Document Type

Journal Article

Publication Date

11-2-2018

Journal

OncoImmunology

Volume

7

Issue

11

DOI

10.1080/2162402X.2018.1500107

Keywords

adipocyte; Breast cancer; combination therapy; immune checkpoint; immunotherapy; inflammation and cancer; new targets; PD-1; PD-L1; PPARgamma antagonist

Abstract

Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. 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.

APA Citation

Wu, B., Sun, X., Gupta, H., Yuan, B., Li, J., Ge, F., Chiang, H., Zhang, X., Zhang, C., Zhang, D., Yang, J., Hu, Y., Curiel, T., & Li, R. (2018). Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer. OncoImmunology, 7 (11). http://dx.doi.org/10.1080/2162402X.2018.1500107