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INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN-γ signaling

文献类型：期刊论文

作者Li, Fang-lin4,5; Gu, Long-hua4,5; Tong, Yong-liang4,5; Chen, Run-qiu3,5; Chen, Shi-yi2; Yu, Xiao-lu4,5; Liu, Nan4,5; Lu, Jiang-ling4,5; Si, Yuan4,5; Sun, Jian-hua1,5
刊名ACTA PHARMACOLOGICA SINICA
出版日期2024-09-02
页码14
关键词cancer immunotherapy INHBA Activin A IFN-gamma signaling pathway PD-L1
ISSN号1671-4083
DOI10.1038/s41401-024-01381-x
通讯作者Long, Yi-ru(s18-longyiru@simm.ac.cn) ; Gong, Li-kun(lkgong@simm.ac.cn)
英文摘要Inhibin beta A (INHBA) and its homodimer activin A have pleiotropic effects on modulation of immune responses and tumor progression, but it remains uncertain whether tumors may release activin A to regulate anti-tumor immunity. In this study we investigated the effects and mechanisms of tumor intrinsic INHBA on carcinogenesis, tumor immunity and PD-L1 blockade. Bioinformatic analysis on the TCGA database revealed that INHBA expression levels were elevated in 33 cancer types, including breast cancer (BRCA) and colon adenocarcinoma (COAD). In addition, survival analysis also corroborated that INHBA expression was negatively correlated with the prognosis of many types of cancer patients. We demonstrated that gain or loss function of Inhba did not alter in vitro growth of colorectal cancer CT26 cells, but had striking impact on mouse tumor models including CT26, MC38, B16 and 4T1 models. By using the TIMER 2.0 tool, we figured out that in most cancer types, Inhba expression in tumors was inversely associated with the infiltration of CD4+ T and CD8+ T cells. In CT26 tumor-bearing mice, overexpression of tumor INHBA eliminated the anti-tumor effect of the PD-L1 antibody atezolizumab, whereas INHBA deficiency enhanced the efficacy of atezolizumab. We revealed that tumor INHBA significantly downregulated the interferon-gamma (IFN-gamma) signaling pathway. Tumor INHBA overexpression led to lower expression of PD-L1 induced by IFN-gamma, resulting in poor responsiveness to anti-PD-L1 treatment. On the other hand, decreased secretion of IFN-gamma-stimulated chemokines, including C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10), impaired the infiltration of effector T cells into the tumor microenvironment (TME). Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy with garetosmab or atezolizumab. We demonstrate that INHBA and activin A are involved in anti-tumor immunity by inhibiting the IFN-gamma signaling pathway, which can be considered as potential targets to improve the responsive rate of PD-1/PD-L1 blockade.
WOS关键词REGULATORY T-CELLS ; ACTIVIN-A ; INTERFERON-GAMMA ; ALTERNATIVE ACTIVATION ; EXPRESSION ; CYTOKINE ; CANCER ; DIFFERENTIATION ; TRANSCRIPTION
资助项目Shanghai Science and Technology Committee[22S11902100] ; Zhongshan Municipal Bureau of Science and Technology[2020SYF08] ; Department of Science and Technology of Guangdong Province[2019B090904008] ; Department of Science and Technology of Guangdong Province[2021B0909050003] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA 12050305]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001302967400002
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/313062]  
专题新药研究国家重点实验室
通讯作者Long, Yi-ru; Gong, Li-kun
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Fudan Univ, Sch Pharm, Dept Microbiol & Biochem Pharm, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Li, Fang-lin,Gu, Long-hua,Tong, Yong-liang,et al. INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN-γ signaling[J]. ACTA PHARMACOLOGICA SINICA,2024:14.
APA Li, Fang-lin.,Gu, Long-hua.,Tong, Yong-liang.,Chen, Run-qiu.,Chen, Shi-yi.,...&Gong, Li-kun.(2024).INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN-γ signaling.ACTA PHARMACOLOGICA SINICA,14.
MLA Li, Fang-lin,et al."INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN-γ signaling".ACTA PHARMACOLOGICA SINICA (2024):14.

入库方式： OAI收割

来源：上海药物研究所

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