肿瘤相关成纤维细胞CAF分泌CXCL12诱导CXCR4+MDSC聚集促进胃癌免疫逃逸的作用及机制研究

Immunotherapy resistance caused by immune escape is the key problem need to be solved in the comprehensive treatment of gastric cancer. The immune suppressive microenvironment of gastric cancer formed by the interaction between Cancer Associated Fibroblasts (CAF) and Myeloid-Derived Suppressor Cells (MDSC) plays an important role in the tumor immune escape. Our previous study has identified that CXCL12/CXCR4 signaling pathway could promote the progression of gastric cancer and induce the chemotherapy resistance of 5-fluorouracil through activating PAK1 (National Natural Science Foundation of China, 81501999). Further studies conclusively showed that there is an increase of the cell count of infiltrated CAF and CXCR4 positive MDSC (CXCR4+MDSC) in the interstitial tissue of gastric cancer patients with high expression of CXCL12, and the expression level of CXCL12 is significantly correlated with the number of infiltrating CAF and CXCR4+MDSC. In addition, CXCL12/CXCR4 signaling pathway in CXCR4+MDSC could also activate PAK1, increase the expression of TGF-β1, and further enhance the immunosuppressive function of CXCR4+MDSC. On the basis of previous studies, this project will further clarify the molecular mechanisms underlying the tumor-promoting effects of CXCL12 secreted by CAF, which could induces CXCR4+MDSC accumulation in tumor tissue, enhances its immunosuppressive function, and promotes immune escape of gastric cancer through the stimulation of CXCL12/CXCR4 signaling pathway in CXCR4+MDSC. This project will construct a model of molecular typing of CXCR4+MDSC in the microenvironment of gastric cancer, help us lay the theoretical foundation for the development of targeted therapeutic drugs, and provide a new idea for the exploration of the predictor of immunotherapy efficacy for gastric cancer.

免疫逃逸是胃癌综合治疗中亟待解决的关键问题，胃癌组织中肿瘤相关成纤维细胞（CAF）与骨髓来源的抑制性细胞（MDSC）相互作用形成的免疫抑制微环境在其中扮演关键角色。我们前期研究发现： CXCL12/CXCR4信号通路的活化可以促进胃癌进展及5-FU化疗抵抗（青年基金，81501999）。进一步研究发现：高表达CXCL12的胃癌组织中CAF和CXCR4+MDSC的浸润增加，并且CXCL12的表达水平与CAF和CXCR4+MDSC的浸润细胞数量正相关。此外，CXCR4+MDSC中CXCL12/CXCR4信号通路的活化还可以增加免疫抑制因子TGF-β1的表达。本申请项目拟在前期发现的基础上，阐述胃癌微环境中CAF通过分泌CXCL12，诱导CXCR4+MDSC在胃癌组织中聚集并活化，促进胃癌免疫逃逸的现象及其分子机制，构建胃癌微环境中MDSC分子分型模型，为进一步开发新型免疫治疗药物奠定理论基础。

肿瘤微环境的形成是肿瘤细胞与间质相互作用的结果，其中免疫细胞和免疫相关分子发挥了重要的作用。肿瘤浸润免疫细胞能够感知肿瘤微环境中来自肿瘤细胞或间质的上游刺激信号发生功能重塑，分化为不同的功能亚群，进而分泌调节性细胞因子影响下游效应性免疫细胞的功能状态，最终促进肿瘤免疫逃逸、影响患者免疫治疗反应性。在本项目资助下，项目负责人对肿瘤微环境中免疫细胞和免疫相关分子进行了一系列深入的研究。研究发现：（1）胃癌组织中IL-10+肿瘤相关巨噬细胞（TAM）的数量与患者的预后及对化疗的反应负相关。IL-10+TAM促进胃癌免疫抑制微环境的形成，抑制IL-10+TAM的作用有望成为新的胃癌治疗方法。（Annals of Surgery. 2022）；（2）胃癌组织中Latency-associated Peptide（LAP）的高表达与胃癌患者的不良预后相关。胃癌组织中LAP高表达的患者对以氟尿嘧啶为基础的化疗不敏感。LAP通过抑制CD8+T细胞的浸润促进胃癌免疫抑制微环境的形成，LAP有望成为新的胃癌治疗靶点。（Annals of Surgery. 2022）；（3）胃癌微环境中过量表达的CD73与效应性CD8+T细胞功能耗竭紧密相关。在CD73高表达的胃癌患者中，CD8+T细胞免疫检查点分子PD-1表达上调，而IFN-γ、Perforin等效应分子分泌则显著减少，从而促进胃癌免疫逃逸，提示患者不良预后以及免疫治疗抵抗。（European Journal of Cancer. 2021）；（4）胃癌组织中肿瘤浸润嗜碱粒细胞（Tumor-infiltrating basophils，TIB）的数量与患者的预后及对化疗的反应负相关。TIB促进胃癌免疫抑制微环境的形成，抑制TIB的作用有望成为新的胃癌治疗方法。（Annals of Surgical Oncology. 2021）；（5）胃癌组织中巨噬细胞分泌的CXCL8通过PD-L1+巨噬细胞促进胃癌免疫抑制微环境的形成，抑制CXCL8的表达可以发挥抗肿瘤的作用，CXCL8抑制剂有望成为新的胃癌治疗方法。（Gut. 2019）。上述研究结果使我们更深入、全面的了解胃癌的免疫调控机制，为精确筛选免疫治疗敏感患者、扩大免疫治疗获益人群奠定理论基础。