Qian Liang, Wu Ling, Miao Xiaohui, Xu Jiao, Zhou Yao
Department of Respiratory and Critical Care Medicine, WuJin Hospital Afliated With Jiangsu University, WuJin Clinical College of Xuzhou Medical University, No.2, Yongning North Road, Changzhou, 213017, Jiangsu, China.
Apoptosis. 2025 Apr;30(3-4):784-804. doi: 10.1007/s10495-024-02052-2. Epub 2024 Dec 26.
The treatment of non-small cell lung cancer (NSCLC) remains a critical challenge in oncology, primarily due to the dysfunction and exhaustion of T cells within the tumor microenvironment, which greatly limits the effectiveness of immunotherapy. This study investigates the regulatory role of the T cell immunoglobulin and ITIM domain (TIGIT)-CD226-PVR signaling axis in the exhaustion and apoptosis of cluster of differentiation (CD)27+/CD127+T cells in NSCLC. Utilizing single-cell sequencing technology, we conducted a comprehensive gene expression analysis of T cells in a mouse model of NSCLC. Bioinformatics analysis revealed that the TIGIT-CD226-PVR signaling axis is highly active in the CD27+/CD127+T cell subset and is closely associated with their functional decline and exhaustion. In vitro experiments further demonstrated that inhibiting the TIGIT-PVR pathway while activating the CD226-PVR pathway significantly restored T cell proliferation and effector function. Importantly, in vivo studies showed that targeting this axis can significantly alleviate T cell exhaustion, enhance their cytotoxicity against NSCLC cells, and promote apoptosis, thereby improving the efficacy of immunotherapy.
非小细胞肺癌（NSCLC）的治疗仍然是肿瘤学中的一项关键挑战，主要是由于肿瘤微环境中T细胞的功能障碍和耗竭，这极大地限制了免疫疗法的有效性。本研究调查了T细胞免疫球蛋白和ITIM结构域（TIGIT）-CD226-PVR信号轴在NSCLC中分化簇（CD）27+/CD127+T细胞耗竭和凋亡中的调节作用。利用单细胞测序技术，我们对NSCLC小鼠模型中的T细胞进行了全面的基因表达分析。生物信息学分析表明，TIGIT-CD226-PVR信号轴在CD27+/CD127+T细胞亚群中高度活跃，并且与其功能衰退和耗竭密切相关。体外实验进一步证明，抑制TIGIT-PVR途径同时激活CD226-PVR途径可显著恢复T细胞增殖和效应功能。重要的是，体内研究表明，靶向该信号轴可显著减轻T细胞耗竭，增强其对NSCLC细胞的细胞毒性，并促进细胞凋亡，从而提高免疫疗法的疗效。
