GNG4调节趋化因子CXCL13/CXCR5信号增加T细胞浸润肿瘤机制研究

CAR-T细胞治疗是肿瘤免疫治疗的新策略。理想的CAR-T细胞治疗需要足够数量的T细胞浸润肿瘤，触发肿瘤微环境中由内至外的系统性免疫杀伤作用。现阶段，CAR-T治疗已在癌症治疗中体现出其优越性。但T细胞无法有效浸润实体肿瘤是限制其在实体瘤中应用的关键因素。我们前期研究发现，GNG4在杀伤性肿瘤特异性T细胞中高表达在正常组织T细胞中低表达。趋化因子CXCL13与GNG4在同一T细胞亚群共表达。据此，我们提出假说：GNG4调节趋化因子信号CXCL13/CXCR5信号增加了T细胞浸润肿瘤。我们近期研究证明，过表达GNG4的T细胞相比于对照能进一步增加小鼠体内肿瘤浸润T细胞的数量。在此基础上，我们拟在分子水平，细胞水平，动物水平设计实验，通过CO-IP，二代测序等手段，阐明GNG4调节CXCL13/CXCR5信号增加T细胞浸润肿瘤的机制。本项目可为CAR-T疗法对实体瘤的治疗提供新的方案。

CAR-T cell therapy has become a new way of tumor immunotherapy. An ideal CAR-T cell therapy requires a sufficient number of T cells to infiltrate the tumor. It triggers systemic immune killing from inside out in tumor microenvironment. At present, owing to T cells can not effectively infiltrate the tumor, CAR-T cell therapy is difficult to achieve good effect in the treatment of solid tumors. Our previous study found that GNG4 was highly expressed in tumor specific T cells, low expressed in immunosuppressive regulatory T cells, and low expressed in normal tissue T cells. Besides, CXCL13 and GNG4 were co expressed in the same T cell subgroup. Therefore, we hypothesized that GNG4 regulates chemokine signaling and CXCL13 / CXCR5 signaling, which increases T cell infiltration. Our recent study further demonstrated that GNG4 overexpressing CD8+ T cells can further increase the number of tumor infiltrating T cells in mice compared with the control group. On this basis, we plan to design experiments at the molecular level, cell level and animal level to elucidate the mechanism of GNG4 regulating CXCL13 / CXCR5 signal by means of CO-IP, second generation sequencing and mass spectrometry. Thus, this project provides a new scheme for CAR-T cell therapy in the treatment of solid tumors.