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.
| Language | English (US) |
|---|---|
| Journal | OncoImmunology |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
| Externally published | Yes |
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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 journal › Article
}
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 -