抑制素 β A (INHBA) 及其同型二聚体激活素 A 对调节免疫反应和肿瘤进展具有多效性，但肿瘤是否可以释放激活素 A 来调节抗肿瘤免疫仍不确定。在本研究中，我们研究了肿瘤内在INHBA对癌发生、肿瘤免疫和PD-L1阻断的影响和机制。 TCGA 数据库的生物信息分析显示，INHBA 表达水平在 33 种癌症类型中升高，包括乳腺癌 (BRCA) 和结肠腺癌 (COAD)。此外，生存分析也证实INHBA表达与多种类型癌症患者的预后呈负相关。我们证明，Inhba 功能的获得或丧失不会改变结直肠癌 CT26 细胞的体外生长，但对小鼠肿瘤模型（包括 CT26、MC38、B16 和 4T1 模型）产生显着影响。通过使用TIMER 2.0工具，我们发现在大多数癌症类型中，肿瘤中的Inhba表达与CD4 T和CD8 T细胞的浸润呈负相关。在 CT26 荷瘤小鼠中，肿瘤 INHBA 的过度表达消除了 PD-L1 抗体 atezolizumab 的抗肿瘤作用，而 INHBA 缺乏则增强了 atezolizumab 的疗效。我们发现肿瘤 INHBA 显着下调干扰素-γ (IFN-γ) 信号通路。肿瘤INHBA过表达导致IFN-γ诱导的PD-L1表达降低，导致抗PD-L1治疗反应较差。另一方面，IFN-γ刺激的趋化因子（包括C-X-C基序趋化因子9（CXCL9）和10（CXCL10））的分泌减少，损害了效应T细胞向肿瘤微环境（TME）的浸润。此外，激活素A特异性抗体garetosmab改善了抗肿瘤免疫力，其与抗PD-L1抗体atezolizumab的组合显示出优于garetosmab或atezolizumab单一疗法的治疗效果。我们证明INHBA和激活素A通过抑制IFN-γ信号通路参与抗肿瘤免疫，这可以被认为是提高PD-1/PD-L1阻断反应率的潜在靶点。© 2024。作者(s)，经中国科学院上海药物研究所和中国药理学会独家授权。

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.