肿瘤相关中性粒细胞通过G-CSF-PD-L2通路介导免疫抑制以及促进胃癌进展的作用及机制研究

Neutrophils are prominent components of immune cell types in gastric cancer (GC) tumors. However, the role and mechanism of tumor-associated neutrophils foster immune suppression and gastric cancer progression in human GC are presently unknown. Previously, we found that GC-associated neutrophils suppress T-cell’s anti-tumor function and expressed high level immunosuppressive molecule programmed death-ligand 2 (PD-L2), suggesting that these GC-associated neutrophils might foster immune suppression and gastric cancer progression through PD-L2. Thus, we aim at these GC-associated neutrophils, and intend to investigate (1) the clinical significance and role of PD-L2 expression on these GC-associated neutrophils in human GC; (2) the regulating mechanism of PD-L2 expression on these GC-associated neutrophils and activation of these GC-associated neutrophils by tumor microenvironment-derived G-CSF; (3) the effector mechanism of these GC-associated neutrophils in the fostering immune suppression and gastric cancer progression through PD-L2; by using obtained clinic specimens, isolated or cultured primary tissues or cells, and In vivo GC mice models, and also in terms of cytology, immunology and molecular biology technology. This study may provide new experimental evidence for the immunopathological mechanism of GC microenvironment and clinic treatment of targeting at these GC-associated neutrophils.

肿瘤相关中性粒细胞是胃癌微环境中重要的免疫细胞类型之一；但其介导病理性免疫抑制进而促进胃癌进展的机制尚不清楚。前期发现，胃癌相关中性粒细胞可以显著抑制T淋巴细胞的抗肿瘤相关免疫功能并高表达免疫抑制性分子PD-L2，提示胃癌相关中性粒细胞很可能通过PD-L2参与介导了病理性免疫抑制并促进了胃癌进展。因此，本项目拟以此胃癌相关中性粒细胞为研究对象，利用临床新鲜标本获得、原代组织/细胞分离培养及胃癌动物模型，运用细胞学、免疫学及分子生物学等技术，（1）明确PD-L2在胃癌相关中性粒细胞表达的临床意义；（2）揭示胃癌微环境中G-CSF激活并诱导中性粒细胞表达PD-L2的调控机制；（3）阐明胃癌相关中性粒细胞通过PD-L2介导病理性免疫抑制以及促进胃癌进展的效应机制。相关研究将为胃癌微环境免疫病理机制的阐明和靶向胃癌相关中性粒细胞的临床治疗提供新的实验证据。

肿瘤相关中性粒细胞是胃癌微环境中重要的免疫细胞类型之一，但其介导病理性免疫抑制进而促进胃癌进展的机制尚不清楚。我们前期研究发现，胃癌相关中性粒细胞可以显著抑制T淋巴细胞的抗肿瘤相关免疫功能并高表达免疫抑制性分子PD-L2，提示胃癌相关中性粒细胞很可能通过PD-L2参与介导了病理性免疫抑制并促进了胃癌进展。因此，本项目拟以此胃癌相关中性粒细胞为研究对象，利用临床新鲜标本获得、原代组织/细胞分离培养及胃癌动物模型，运用细胞学、免疫学及分子生物学等技术，明确PD-L2在胃癌相关中性粒细胞表达的临床意义；揭示胃癌微环境中G-CSF激活并诱导中性粒细胞表达PD-L2的调控机制；阐明胃癌相关中性粒细胞通过PD-L2介导病理性免疫抑制以及促进胃癌进展的效应机制。通过本项目系统性研究，从免疫学角度阐明了胃癌微环境中G-CSF和Th17来源的IL-17A分别通过JAK-STAT3和ERK-NF-κB信号通路诱导中性粒细胞表达PD-L2和FasL,胃癌微环境中的PD-L2+FasL+双阳性中性粒细胞分别通过与CD8+T细胞表面PD-1和Fas受体结合进而抑制增殖和免疫功能，促进胃癌免疫抑制微环境的形成。