期刊
ACTA PHARMACEUTICA SINICA B
卷 12, 期 2, 页码 787-800出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2021.07.011
关键词
TGR5; Bile acids; Tumor-associated macrophages (TAMs); Tumor microenvironment (TME); Non-small cell lung cancer (NSCLC); Antitumor immunity; Immunotherapy; cAMP-STAT3/STAT6
资金
- National Natural Science Foundation of China [81874314, 81903633]
- Yangfan project of Shanghai Science and Technology Commission (China) [19YF1428700]
This study reveals the protumor function of TGR5 in non-small cell lung cancer (NSCLC) by regulating tumor-associated macrophage (TAM) polarization and suppressing anti-tumor immunity. Mechanistically, TGR5 promotes the transformation of TAMs into protumorigenic M2-like phenotypes through the activation of the cAMP-STAT3/STAT6 signaling pathway. The study also shows that the expression of TGR5 is associated with TAM infiltration in NSCLC tissues, and the co-expression of TGR5 and high TAM infiltration correlates with the prognosis and overall survival of NSCLC patients.
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. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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