INHBA通过抑制IFN-γ信号传导促进肿瘤的生长，并诱导对PD-L1阻断的抗性
INHBA promotes tumor growth and induces resistance to PD-L1 blockade by suppressing IFN-γ signaling
影响因子:8.40000
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
摘要
抑制蛋白βA（INHBA）及其同二聚体激活素A对免疫反应和肿瘤进展的调节具有多效性影响，但仍然不确定肿瘤是否可以释放激活素A来调节抗肿瘤免疫。在这项研究中，我们研究了肿瘤内在INHBA对癌变，肿瘤免疫和PD-L1阻滞的影响和机制。 TCGA数据库的生物信息学分析表明，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，生存分析还证实了INHBA表达与许多类型的癌症患者的预后负相关。我们证明，INHBA的增益或损失功能不会改变结直肠癌CT26细胞的体外生长，而是对包括CT26，MC38，B16和4T1模型在内的小鼠肿瘤模型产生了惊人的影响。通过使用计时器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细胞的浸润成反比。在含有CT26肿瘤的小鼠中，肿瘤INHBA的过表达消除了PD-L1抗体Atezolizumab的抗肿瘤作用，而INHBA缺乏症增强了阿托佐伊珠单抗的疗效。我们揭示了肿瘤INHBA显着下调了干扰素-γ（IFN-γ）信号通路。肿瘤INHBA过表达导致IFN-γ诱导的PD-L1的表达较低，导致对抗PD-L1处理的反应不佳。另一方面，IFN-γ刺激的趋化因子的分泌减少，包括C-X-C基序趋化因子9（CXCL9）和10（CXCL10），损害了效应T细胞浸润到肿瘤微环境（TME）中。此外，活化素A特异性抗体GaretoSmAB改善了抗肿瘤免疫，与抗PD-L1抗体atezolizumab的结合表现出对与Garetosmab或Atezolizumab单一疗法的优势治疗作用。我们证明，INHBA和活化素A通过抑制IFN-γ信号通路参与抗肿瘤免疫，这可以被视为提高PD-1/PD-L1阻滞响应速率的潜在靶标。
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.