Wu Dongjuan, Fan Yaohua, Zhang Mingsheng, Wang Xiaoguang, He Xuesong, Guo Xinwei, Liu Yangchen, Cao Chenxi, Deng Zhaoqun
Department of Oncology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China.
Department of Oncology, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, Hubei, China.
Front Immunol. 2025 Jun 20;16:1598436. doi: 10.3389/fimmu.2025.1598436. eCollection 2025.
Programmed death 1 (PD-1) and its ligand PD-L1 inhibitors and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies have been approved for the treatment of advanced hepatocellular carcinoma (HCC), but the response rates of these immunotherapy are not high, and they are easy to be resistant. Studies have shown that the gut microbiota can significantly influence immune responses and the efficacy of immune checkpoint inhibitors (ICIs). The aim of this study is to investigate whether the combination therapy of Tumor-Suppressing Multi-Enterobacteria (TSME) and PD-L1 inhibitor (atezolizumab) can improve the efficacy of immunotherapy-resistant hepatocellular carcinoma.
Patients with advanced liver cancer resistant to atezolizumab were treated with tumor suppressor TSME combined with atezolizumab, and the efficacy was evaluated. By establishing a tumor-bearing mouse model, the control group, InVivoMAb anti-mouse PD-1 monotherapy group, TSME group, and anti-PD-1 mab +TSME double drug group were set up. To evaluate whether the combination therapy enhances the antitumor effect, the proportion of T cells in the tumor microenvironment (TME) was analyzed by immunohistochemistry.
Patients with clinically immuno-resistant hepatocellular carcinoma who were treated with TSME still had a PFS of about 7 months with continued atezolizumab treatment, and they were still in long-term survival. The model showed that TSME combined with αPD-1 promoted the efficacy of anti-PD-1 antibody immunotherapy by increasing the proportion of CD8 T cells and CD4 T cells in the tumor microenvironment and reducing the proportion of regulatory T cells (Tregs) compared with TSME alone or αPD-1 alone. The relative tumor inhibition rate (TGI) of αPD-1+TSME combination group was as high as 58.78% ± 7.55%. Tumor volume was lower in the αPD-1+TSME group than in the monotherapy group.
Anti-tumor TSME combined with αPD-1 mAb may be a new strategy to improve the sensitivity of immune-resistant patients with advanced hepatocellular carcinoma to anti-PD-1 immunotherapy.
程序性死亡蛋白1（PD-1）及其配体PD-L1抑制剂以及细胞毒性T淋巴细胞相关抗原4（CTLA-4）单克隆抗体已被批准用于治疗晚期肝细胞癌（HCC），但这些免疫疗法的有效率不高，且易产生耐药性。研究表明，肠道微生物群可显著影响免疫反应及免疫检查点抑制剂（ICI）的疗效。本研究旨在探讨抑癌多肠杆菌（TSME）与PD-L1抑制剂（阿替利珠单抗）联合治疗能否提高对免疫治疗耐药的肝细胞癌的疗效。
对阿替利珠单抗耐药的晚期肝癌患者采用抑癌TSME联合阿替利珠单抗进行治疗，并评估疗效。通过建立荷瘤小鼠模型，设置对照组、InVivoMAb抗小鼠PD-1单药治疗组、TSME组以及抗PD-1单抗+TSME双药组。为评估联合治疗是否增强抗肿瘤作用，采用免疫组化分析肿瘤微环境（TME）中T细胞的比例。
接受TSME治疗的临床免疫耐药肝细胞癌患者继续使用阿替利珠单抗治疗后，无进展生存期仍约为7个月，且仍处于长期生存状态。模型显示，与单独使用TSME或αPD-1相比，TSME联合αPD-1通过增加肿瘤微环境中CD8 T细胞和CD4 T细胞的比例以及降低调节性T细胞（Tregs）的比例，促进了抗PD-1抗体免疫治疗的疗效。αPD-1+TSME联合组的相对肿瘤抑制率（TGI）高达58.78%±7.55%。αPD-1+TSME组的肿瘤体积低于单药治疗组。
抗肿瘤TSME联合αPD-1单抗可能是提高晚期免疫耐药肝细胞癌患者对抗PD-1免疫治疗敏感性的新策略。
Zotero 插件
