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

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

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.

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Fig. 1: INHBA promoted tumor growth via T cell-related immunity.
Fig. 2: INHBA induced resistance to anti-PD-L1 antibody.
Fig. 3: INHBA inhibited IFN-γ response pathway.
Fig. 4: INHBA suppressed IFNGR expression on tumor.
Fig. 5: INHBA suppressed PD-L1 expression on tumor via IFN-γ pathway.
Fig. 6: INHBA promoted tumor growth by suppressing secretion of CXCL9 and CXCL10.
Fig. 7: Anti-activin A antibody could suppress tumor growth and enhance responsiveness to anti-PD-L1 antibody.
Fig. 8: The summary of role of tumor INHBA in regulating tumor immunity and anti-PD-L1 therapy.

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Acknowledgements

All the figures were created with BioRender.com. This work was supported by Shanghai Science and Technology Committee (22S11902100), Zhongshan Municipal Bureau of Science and Technology (2020SYF08), the Department of Science and Technology of Guangdong Province (2019B090904008 and 2021B0909050003), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA 12050305).

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Authors and Affiliations

  1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Fang-lin Li, Long-hua Gu, Yong-liang Tong, Run-qiu Chen, Xiao-lu Yu, Nan Liu, Jiang-ling Lu, Yuan Si, Jian-hua Sun, Jing Chen, Yi-ru Long & Li-kun Gong

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Fang-lin Li, Long-hua Gu, Yong-liang Tong, Xiao-lu Yu, Nan Liu, Jiang-ling Lu, Yuan Si, Jing Chen, Yi-ru Long & Li-kun Gong

  3. Department of Microbiological and Biochemical Pharmacy, School of Pharmacy, Fudan University, Shanghai, 201203, China

    Run-qiu Chen

  4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Shi-yi Chen

  5. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China

    Jian-hua Sun & Li-kun Gong

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Contributions

FLL, YRL carried out the ideas and designed the studies; FLL, LHG, SYC, JLL, YS conducted the experiments, acquired the data and documented data analysis; YLT, RQC, XLY, NL contributed new agents or analytic tools; FLL interpreted results and plotted figures; JC, JHS, LKG acquired funding; FLL, YRL, LKG drafted, revised and approved the final version of the manuscript.

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Correspondence to Yi-ru Long or Li-kun Gong.

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Li, Fl., Gu, Lh., Tong, Yl. et al. INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN-γ signaling. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01381-x

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