索拉非尼通过VEGFR/AKT/Foxo1信号通路促进调节性T细胞分化，从而削弱其在肝癌中的疗效。
Sorafenib Promotes Treg Cell Differentiation To Compromise Its Efficacy via VEGFR/AKT/Foxo1 Signaling in Hepatocellular Carcinoma.
作者信息
Shen Yingying, Wang Hanliang, Ma Zeyu, Hao Minyan, Wang Shuowang, Li Junwei, Fang Yue, Yu Lei, Huang Yingying, Wang Changrong, Xiang Jingjing, Cai Zhijian, Wang Jianli, Jin Hongchuan, Zhou Jia, Guo Jufeng, Ying Pingting, Wang Xian
机构信息
Department of Medical Oncology, Zhejiang Key Laboratory of Multi-omics Precision Diagnosis and Treatment of Liver Diseases, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang, China.
Department of Dermatology and Venerology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang, China.
出版信息
Cell Mol Gastroenterol Hepatol. 2025;19(5):101454. doi: 10.1016/j.jcmgh.2024.101454. Epub 2024 Dec 30.
BACKGROUND & AIMS: Sora is the first-line drug for advanced hepatocellular carcinoma (HCC). However, acquired resistance to Sora treatment largely hinders its therapeutic efficacy, and the mechanisms underlying Sora resistance remain poorly understood. Here, we revealed a new mechanism by which Sora promotes the differentiation of regulatory T (Treg) cells to suppress the immune response in the HCC tumor microenvironment (TME) and induce Sora resistance.
METHODS
Human liver tissues were obtained from HCC patients. Female C57BL/6J, OT-II, and Foxp3 mice were also used. Flow cytometry was used to analyze immune cells in TME. Flow cytometry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay were performed to evaluate Treg cell differentiation. Immunoblotting was conducted to identify relevant proteins. Mouse and human tumor tissues were evaluated via multiplex immunofluorescence staining. Sora-treated HCC tissues and Sora-treated Treg cells were subjected to RNA sequencing analysis. Tumor models were generated and treated with Sora, Sora combined with an anti-CD25 antibody, or Sora combined with the Foxo1 inhibitor AS1842856.
RESULTS
First, we found through bioinformatic analysis that Sora suppresses the immune response in HCC. Furthermore, Sora increased the Treg cell population to promote the formation of an immunosuppressive TME in HCC. In vitro, Sora promoted Treg cell differentiation and increased the immunosuppressive activity of Treg cells. Activating VEGF and AKT abolished the effect of Sora on Treg cell differentiation, whereas inhibiting Foxo1 compromised Sora-induced Treg cell differentiation, indicating that the induction of Treg cells by Sora is dependent on the VEGFR/AKT/Foxo1 pathway. Finally, Treg inactivation by an anti-CD25 antibody or the Foxo1 inhibitor AS1842856 in combination with Sora showed greater efficacy in the treatment of HCC.
CONCLUSIONS
Sora induced Treg cell differentiation by inhibiting VEGFR/AKT signaling and activating Foxo1, thus suppressing the immune response and reducing Sora efficacy. Treg inactivation might be a promising strategy to alleviate the immunosuppressive TME and overcome Sora resistance.
背景与目的
索拉非尼是晚期肝细胞癌（HCC）的一线药物。然而，对索拉非尼治疗产生的获得性耐药在很大程度上阻碍了其治疗效果，且索拉非尼耐药的潜在机制仍知之甚少。在此，我们揭示了一种新机制，即索拉非尼通过促进调节性T（Treg）细胞分化来抑制HCC肿瘤微环境（TME）中的免疫反应并诱导索拉非尼耐药。
方法
从HCC患者获取人肝组织。还使用了雌性C57BL/6J、OT-II和Foxp3小鼠。采用流式细胞术分析TME中的免疫细胞。进行流式细胞术、实时聚合酶链反应和酶联免疫吸附测定以评估Treg细胞分化。进行免疫印迹以鉴定相关蛋白。通过多重免疫荧光染色评估小鼠和人肿瘤组织。对索拉非尼处理的HCC组织和索拉非尼处理的Treg细胞进行RNA测序分析。建立肿瘤模型并用索拉非尼、索拉非尼联合抗CD25抗体或索拉非尼联合Foxo1抑制剂AS1842856进行治疗。
结果
首先，我们通过生物信息学分析发现索拉非尼抑制HCC中的免疫反应。此外，索拉非尼增加Treg细胞群体，以促进HCC中免疫抑制性TME的形成。在体外，索拉非尼促进Treg细胞分化并增加Treg细胞的免疫抑制活性。激活VEGF和AKT消除了索拉非尼对Treg细胞分化的影响，而抑制Foxo1则损害了索拉非尼诱导的Treg细胞分化，表明索拉非尼诱导Treg细胞依赖于VEGFR/AKT/Foxo1途径。最后，抗CD25抗体或Foxo1抑制剂AS1842856与索拉非尼联合使Treg失活在HCC治疗中显示出更大疗效。
结论
索拉非尼通过抑制VEGFR/AKT信号传导并激活Foxo1诱导Treg细胞分化，从而抑制免疫反应并降低索拉非尼疗效。使Treg失活可能是减轻免疫抑制性TME并克服索拉非尼耐药的一种有前景的策略。
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