INHBA促进肿瘤生长并通过抑制IFN-γ信号通路诱导PD-L1阻断耐药
INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN-γ signaling
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影响因子:8.4
分区:医学2区 / 药学1区 化学：综合2区
发表日期:2025 Feb
作者:
Fang-Lin Li, Long-Hua Gu, Yong-Liang Tong, Run-Qiu Chen, Shi-Yi Chen, Xiao-Lu Yu, Nan Liu, Jiang-Ling Lu, Yuan Si, Jian-Hua Sun, Jing Chen, Yi-Ru Long, Li-Kun Gong
DOI:
10.1038/s41401-024-01381-x
摘要
抑制素βA（INHBA）及其同源二聚体促生素A（activin A）在调节免疫反应和肿瘤进展中具有多效性，但肿瘤是否通过分泌促生素A调控抗肿瘤免疫仍未明确。本研究探讨了肿瘤内源性INHBA对癌变、肿瘤免疫及PD-L1阻断的影响机制。通过对TCGA数据库的生物信息学分析发现，INHBA在包括乳腺癌（BRCA）和结直肠腺癌（COAD）在内的33种癌症中的表达升高，且其表达与多种癌症患者预后呈负相关。实验证明，Inhba的过表达或敲除未改变结直肠癌CT26细胞的体外生长，但对小鼠肿瘤模型（包括CT26、MC38、B16和4T1）影响显著。利用TIMER 2.0工具分析发现，绝大多数癌症中，肿瘤中的Inhba表达与CD4+ T细胞和CD8+ T细胞的浸润呈负相关。在CT26肿瘤模型中，过表达肿瘤INHBA抑制了抗肿瘤的PD-L1抗体阿替利珠单抗（atezolizumab）的效果，而INHBA缺失则增强了其疗效。研究还显示，肿瘤INHBA显著下调干扰素γ（IFN-γ）信号通路。INHBA过表达导致由IFN-γ诱导的PD-L1表达降低，导致抗PD-L1治疗反应变差。同时，IFN-γ刺激下的趋化因子（如CXCL9和CXCL10）分泌减少，削弱了效应T细胞向肿瘤微环境的浸润。使用特异性抗体garetosmab抑制促生素A，改善抗肿瘤免疫，并与抗PD-L1抗体联合应用，效果优于单药治疗。研究结果表明，INHBA及促生素A通过抑制IFN-γ信号通路参与抗肿瘤免疫，可能成为改善PD-1/PD-L1阻断疗效的潜在靶点。
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.