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

Bogang Wu, Xiujie Sun, Harshita B. Gupta, Bin Yuan, Jingwei Li, Fei Ge, Huai Chin Chiang, Xiaowen Zhang, Chi Zhang, Deyi Zhang, Jing Yang, Yanfen Hu, Tyler J. Curiel, Rong Li

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
JournalOncoImmunology
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Immunotherapy
Breast Neoplasms
Ligands
Adipocytes
Adipose Tissue
Antibodies
Programmed Cell Death 1 Receptor
Immunity
Adipogenesis
Clinical Trials
T-Lymphocytes

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer. / Wu, Bogang; Sun, Xiujie; Gupta, Harshita B.; Yuan, Bin; Li, Jingwei; Ge, Fei; Chiang, Huai Chin; Zhang, Xiaowen; Zhang, Chi; Zhang, Deyi; Yang, Jing; Hu, Yanfen; Curiel, Tyler J.; Li, Rong.

In: OncoImmunology, 01.01.2018.

Research output: Contribution to journalArticle

Wu, Bogang ; Sun, Xiujie ; Gupta, Harshita B. ; Yuan, Bin ; Li, Jingwei ; Ge, Fei ; Chiang, Huai Chin ; Zhang, Xiaowen ; Zhang, Chi ; Zhang, Deyi ; Yang, Jing ; Hu, Yanfen ; Curiel, Tyler J. ; Li, Rong. / Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer. In: OncoImmunology. 2018.
@article{19d9d17812b84ff689ff444b7d96e545,
title = "Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer",
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.",
keywords = "adipocyte, Breast cancer, combination therapy, immune checkpoint, immunotherapy, inflammation and cancer, new targets, PD-1, PD-L1, PPARgamma antagonist",
author = "Bogang Wu and Xiujie Sun and Gupta, {Harshita B.} and Bin Yuan and Jingwei Li and Fei Ge and Chiang, {Huai Chin} and Xiaowen Zhang and Chi Zhang and Deyi Zhang and Jing Yang and Yanfen Hu and Curiel, {Tyler J.} and Rong Li",
year = "2018",
month = "1",
day = "1",
doi = "10.1080/2162402X.2018.1500107",
language = "English (US)",
journal = "OncoImmunology",
issn = "2162-4011",
publisher = "Landes Bioscience",

}

TY - JOUR

T1 - Adipose PD-L1 Modulates PD-1/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer

AU - Wu, Bogang

AU - Sun, Xiujie

AU - Gupta, Harshita B.

AU - Yuan, Bin

AU - Li, Jingwei

AU - Ge, Fei

AU - Chiang, Huai Chin

AU - Zhang, Xiaowen

AU - Zhang, Chi

AU - Zhang, Deyi

AU - Yang, Jing

AU - Hu, Yanfen

AU - Curiel, Tyler J.

AU - Li, Rong

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - adipocyte

KW - Breast cancer

KW - combination therapy

KW - immune checkpoint

KW - immunotherapy

KW - inflammation and cancer

KW - new targets

KW - PD-1

KW - PD-L1

KW - PPARgamma antagonist

UR - http://www.scopus.com/inward/record.url?scp=85052313006&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052313006&partnerID=8YFLogxK

U2 - 10.1080/2162402X.2018.1500107

DO - 10.1080/2162402X.2018.1500107

M3 - Article

JO - OncoImmunology

T2 - OncoImmunology

JF - OncoImmunology

SN - 2162-4011

ER -