KRAS突变通过CXCL11/CXCR3促进组织驻留记忆T细胞凋亡在结直肠癌转移中的作用及机制

KRAS突变的转移性结直肠癌（mCRC）对靶向药物不敏感，严重威胁患者生命。近期研究发现KRAS突变CRC来源的驻留T细胞过继治疗有效延长患者生存，提示KRAS突变可作为CRC免疫治疗的个体化评估指标。但目前KRAS突变CRC的免疫微环境特征和调控机制尚不清楚。本项目临床回顾性研究发现KRAS突变CRC中组织驻留记忆T细胞（TRM）数量显著减少，与CRC转移和预后相关。文献和预实验进一步提示KRAS突变通过激活ERK/EZH2/TCF7转录信号上调CXCL11，后者通过CXCR3促进TRM凋亡。但具体的分子机制仍需进一步证明。本项目拟：①构建KRAS突变自发结直肠癌小鼠模型和细胞模型，进一步明确TRM数量是否与KRAS突变CRC转移相关；②阐明CXCL11/CXCR3是TRM凋亡的关键信号；③探讨KRAS突变上调CXCL11的分子机制。旨在为KRAS突变CRC免疫治疗提供新的靶点。

Metastatic colorectal cancer (mCRC) of KRAS mutation is insensitive to targeted-chemotherapy drugs and poses a serious threat to patients' lives. Recent studies have found that resident T-cell from from KRAS-mutation CRC tissue play an effective role in prolonging patient survival, suggesting that KRAS mutation can be used as an individual evaluation index of CRC immunotherapy. However, to date, the immune micro-environmental characteristics and its regulatory mechanism in KRAS-mutation CRC are not clear. Clinical retrospective studies in this project found a significant decrease in the number of tissue resident memory T-cells (TRM) in KRAS mutant CRC, associated with CRC metastasis and overall survival. Previous study and pre-experiments further suggest that the KRAS mutation raises CXCL11, which promotes TRM apoptosis through CXCR3, by activating the ERK/EZH2/TCF7 transcription signal. However, the specific molecular mechanism still needs further proof. The project proposes: (1) to construct a mouse model and cell model of KRAS mutation spontaneous colorectal cancer, and further clarify whether the number of TRM is related to KRAS mutation CRC metastasis; (2) to clarify that CXCL11/CXCR3 is the key signal of TRM apoptosis; and (3) to explore the molecular mechanism of KRAS mutation upward CXCL11. This research aims to provide new targets for KRAS mutation CRC immunotherapy.