Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533000, China.
Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
Cell Death Dis. 2022 Mar 10;13(3):223. doi: 10.1038/s41419-022-04645-8.
Targeting key genes that play dominant roles in T cell dysfunction is an efficient strategy for cancer immunotherapy. Here, we aimed to investigate the role of TPX2 in the antitumor effect of CD8 + T cells in hepatocellular carcinoma (HCC). Flow cytometry was used to assay the level of cell surface markers and cytokines in T cells, through which we found that TPX2 was downregulated in HCC-infiltrating CD8 + T cells. TPX2 depletion restricted the antitumor activity of CD8 + T cells, and TPX2 overexpression increased the antitumor effect of CD8 + T cells in tumor-bearing Cd8 mice. TPX2 overexpression improved the antitumor function of human CD8 + T cells and response to anti-PD-1 therapy in an HCC patient-derived xenograft (PDX) mouse model with or without anti-PD-1 therapy. In mechanism, TPX2 promotes the phosphorylation of P65, thus increases the level of p-P65 in nuclear, and p-P65 binds to the promoter of CXCR5, activates its transcription, and increases the level of CXCR5 on CD8 + T cells in a TPX2-dependent way. In conclusion, TPX2 maintains the antitumor effect of CD8 + T cells in HCC by regulating CXCR5 via the NF-κB signaling pathway. Increased TPX2 expression in CD8 + T cells exerts synergistic effects with anti-PD-1 therapy, suggesting a promising immunotherapeutic method in HCC.
靶向在 T 细胞功能障碍中起主导作用的关键基因是癌症免疫治疗的一种有效策略。在这里，我们旨在研究 TPX2 在肝癌 (HCC) 中 CD8+T 细胞抗肿瘤作用中的作用。通过流式细胞术检测 T 细胞表面标志物和细胞因子的水平，我们发现 TPX2 在 HCC 浸润的 CD8+T 细胞中下调。TPX2 耗竭限制了 CD8+T 细胞的抗肿瘤活性，而 TPX2 过表达增加了荷瘤 Cd8 小鼠中 CD8+T 细胞的抗肿瘤作用。TPX2 过表达改善了人 CD8+T 细胞的抗肿瘤功能，并在抗 PD-1 治疗或不进行抗 PD-1 治疗的 HCC 患者来源异种移植 (PDX) 小鼠模型中增强了对 PD-1 治疗的反应。在机制上，TPX2 促进 P65 的磷酸化，从而增加核内 p-P65 的水平，p-P65 与 CXCR5 的启动子结合，激活其转录，并以 TPX2 依赖的方式增加 CD8+T 细胞上 CXCR5 的水平。总之，TPX2 通过 NF-κB 信号通路调节 CXCR5 来维持 CD8+T 细胞在 HCC 中的抗肿瘤作用。CD8+T 细胞中 TPX2 表达的增加与抗 PD-1 治疗具有协同作用，提示在 HCC 中具有有前途的免疫治疗方法。
