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

Autor: Li FL; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; University of Chinese Academy of Sciences, Beijing, 100049, China., Gu LH; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; University of Chinese Academy of Sciences, Beijing, 100049, China., Tong YL; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; University of Chinese Academy of Sciences, Beijing, 100049, China., Chen RQ; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; Department of Microbiological and Biochemical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China., Chen SY; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Yu XL; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; University of Chinese Academy of Sciences, Beijing, 100049, China., Liu N; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; University of Chinese Academy of Sciences, Beijing, 100049, China., Lu JL; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; University of Chinese Academy of Sciences, Beijing, 100049, China., Si Y; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; University of Chinese Academy of Sciences, Beijing, 100049, China., Sun JH; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China., Chen J; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.; University of Chinese Academy of Sciences, Beijing, 100049, China., Long YR; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. s18-longyiru@simm.ac.cn.; University of Chinese Academy of Sciences, Beijing, 100049, China. s18-longyiru@simm.ac.cn., Gong LK; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. lkgong@simm.ac.cn.; University of Chinese Academy of Sciences, Beijing, 100049, China. lkgong@simm.ac.cn.; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China. lkgong@simm.ac.cn.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Sep 02. Date of Electronic Publication: 2024 Sep 02.
DOI: 10.1038/s41401-024-01381-x
Abstrakt: 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-γ (IFN-γ) signaling pathway. Tumor INHBA overexpression led to lower expression of PD-L1 induced by IFN-γ, resulting in poor responsiveness to anti-PD-L1 treatment. On the other hand, decreased secretion of IFN-γ-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-γ signaling pathway, which can be considered as potential targets to improve the responsive rate of PD-1/PD-L1 blockade.
(© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
Databáze: MEDLINE
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