Li Fang-Lin, Gu Long-Hua, Tong Yong-Liang, Chen Run-Qiu, Chen Shi-Yi, Yu Xiao-Lu, Liu Nan, Lu Jiang-Ling, Si Yuan, Sun Jian-Hua, Chen Jing, Long Yi-Ru, Gong Li-Kun
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.
Acta Pharmacol Sin. 2025 Feb;46(2):448-461. doi: 10.1038/s41401-024-01381-x. Epub 2024 Sep 2.
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.
抑制素βA（INHBA）及其同型二聚体激活素A对免疫反应的调节和肿瘤进展具有多效性作用，但肿瘤是否会释放激活素A来调节抗肿瘤免疫仍不确定。在本研究中，我们调查了肿瘤内在的INHBA对肿瘤发生、肿瘤免疫和程序性死亡受体配体1（PD-L1）阻断的影响及机制。对癌症基因组图谱（TCGA）数据库的生物信息学分析显示，在包括乳腺癌（BRCA）和结肠腺癌（COAD）在内的33种癌症类型中，INHBA表达水平升高。此外，生存分析也证实，INHBA表达与多种癌症患者的预后呈负相关。我们证明，Inhba功能的获得或缺失并未改变结直肠癌CT26细胞的体外生长，但对包括CT26、MC38、B16和4T1模型在内的小鼠肿瘤模型有显著影响。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Inhba的表达与CD4 T细胞和CD8 T细胞的浸润呈负相关。在携带CT26肿瘤的小鼠中，肿瘤INHBA的过表达消除了PD-L1抗体阿替利珠单抗的抗肿瘤作用，而INHBA缺陷则增强了阿替利珠单抗的疗效。我们发现，肿瘤INHBA显著下调干扰素-γ（IFN-γ）信号通路。肿瘤INHBA的过表达导致IFN-γ诱导的PD-L1表达降低，从而导致对抗PD-L1治疗的反应性较差。另一方面，IFN-γ刺激的趋化因子分泌减少，包括C-X-C基序趋化因子9（CXCL9）和10（CXCL10），损害了效应T细胞向肿瘤微环境（TME）的浸润。此外，激活素A特异性抗体加雷妥单抗改善了抗肿瘤免疫，其与抗PD-L1抗体阿替利珠单抗联合使用显示出比加雷妥单抗或阿替利珠单抗单药治疗更好的治疗效果。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，这可被视为提高PD-1/PD-L1阻断反应率的潜在靶点。
