TGR5 deficiency activates antitumor immunity in non-small cell lung cancer via restraining M2 macrophage polarization.
10.1016/j.apsb.2021.07.011
- Author:
Lifang ZHAO
1
;
Hongyan ZHANG
1
;
Xueqing LIU
1
;
Shan XUE
1
;
Dongfang CHEN
1
;
Jing ZOU
1
;
Handong JIANG
1
Author Information
1. Department of Respiratory and Critical Care Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
- Publication Type:Journal Article
- Keywords:
Antitumor immunity;
BMDMs, bone marrow-derived macrophages;
Bile acids;
CM, conditioned medium;
Immunotherapy;
LLC, Lewis lung carcinoma;
NSCLC, non-small cell lung cancer;
Non-small cell lung cancer (NSCLC);
SD, standard deviation;
TAMs, Tumor-associated macrophages;
TGR5;
TME, tumor microenvironment;
Tumor microenvironment (TME);
Tumor-associated macrophages (TAMs);
WT, wildtype;
cAMP–STAT3/STAT6
- From:
Acta Pharmaceutica Sinica B
2022;12(2):787-800
- CountryChina
- Language:English
-
Abstract:
The bile acid-responsive G-protein-coupled receptor TGR5 is expressed in monocytes and macrophages, and plays a critical role in regulating inflammatory response. Our previous work has shown its role in promoting the progression of non-small cell lung cancer (NSCLC), yet the mechanism remains unclear. Here, using Tgr5-knockout mice, we show that TGR5 is required for M2 polarization of tumor-associated macrophages (TAMs) and suppresses antitumor immunity in NSCLC via involving TAMs-mediated CD8+ T cell suppression. Mechanistically, we demonstrate that TGR5 promotes TAMs into protumorigenic M2-like phenotypes via activating cAMP-STAT3/STAT6 signaling. Induction of cAMP production restores M2-like phenotypes in TGR5-deficient macrophages. In NSCLC tissues from human patients, the expression of TGR5 is associated with the infiltration of TAMs. The co-expression of TGR5 and high TAMs infiltration are associated with the prognosis and overall survival of NSCLC patients. Together, this study provides molecular mechanisms for the protumor function of TGR5 in NSCLC, highlighting its potential as a target for TAMs-centric immunotherapy in NSCLC.
