FGF2调控SPRY1基因表达在食管癌浸润耗竭型T细胞中的作用及机制研究

对8例未经治疗的食管癌组织浸润的T细胞进行单细胞测序，发现SPRY1在两群耗竭型T细胞中特异性上调。SPRY1在CD8+T细胞肿瘤免疫中的作用还知之甚少。前期我们发现SPRY1过表达能够显著下调T细胞在TCR触发后的细胞因子分泌。据此认为SPRY1是耗竭型T细胞的标志基因，其高表达能负向调控耗竭型T细胞TCR的活化。阻断SPRY1可能有助于逆转耗竭型T细胞功能。进一步研究揭示，FGF2上调SPRY1在CD8+T细胞中的表达，且FGF2预处理的T细胞针对TCR激活的应答能力显著降低。推测肿瘤微环境中的FGF2通过上调SPRY1促进T细胞耗竭。本项目将继续研究SPRY1在耗竭型T细胞中的作用机制，探讨肿瘤微环境中的FGF2对T细胞效应的影响，以及FGF2是否通过上调SPRY1的表达促进T细胞耗竭。阐明FGF2-SPRY1轴在抗肿瘤免疫应答中的作用和机制，为其作为肿瘤免疫治疗靶点提供实验依据。

Single-cell sequencing analysis of infiltrating T cells in 8 untreated esophageal cancer revealed that SPRY1 was specifically up-regulated in two groups of exhausted T cells. However, the role of SPRY1 in CD8+T cells, especially its role in regulating T cells in tumor immunity is poorly understood. In our previous work, we found that SPRY1 overexpression could significantly down-regulate T cell cytokine secretion after TCR triggering. Based on this, we believe that SPRY1 is a marker gene for exhausted T cells, and its high expression is also an important factor that negatively regulates TCR activation of exhausted T cells. Therefore, blocking SPRY1 expression may help reverse the effector function of exhausted T cells. Further research revealed that FGF2 up-regulated the expression of SPRY1 in CD8+T cells, and that FGF2 pre-treated T cells significantly reduced the ability to respond to TCR activation. Based on this, we speculate that tumor stroma derived FGF2 promotes T cell exhaustion by up-regulating the expression of SPRY1. In this project, we will continue to study the function and mechanism of SPRY1 in exhausted T cells. In vivo and in vitro experiments will be used to investigate the effect of FGF2 on T cells, and whether this effect dependents on SPRY1 expression. In summary, the aim of this study is to clarify the role and mechanism of FGF2-SPRY1 axis in anti-tumor immune response, and provide experimental basis for it as a tumor immunotherapy target.