基于单细胞转录组测序解析胃癌微环境中CAFs异质性及GPR4+CD36+CAFs亚群促进胃癌免疫逃逸的机制

胃癌是一种高异质性的恶性肿瘤，CAFs具有多种细胞来源，是构成胃癌异质性的重要原因之一。然而胃癌中CAFs异质性程度、产生及其对肿瘤进展的影响仍未阐明。我们前期发现胃癌中CAFs有六个群体，GPR4+CD36+CAFs亚群提示患者的不良预后，其演化与酸性微环境有关，具有交叉抗原呈递功能。基于此，我们提出如下科研假设：胃癌中存在六种异质性CAFs亚群，与胃癌病理特征和预后呈现不同的关系；酸性微环境通过GPR4-cGMP-PKG-MEF2C通路诱导GPR4+CD36+CAFs演化，它表达免疫抑制检查点分子B7-H3和CD155等，通过交叉抗原呈递抑制CD8+T细胞功能，促进胃癌免疫逃逸。本项目将通过研究胃癌CAFs亚群异质性、临床意义、演化的关键节点、GPR4+CD36+CAFs的调控及其促进胃癌免疫逃逸的分子机制，阐明CAFs异质性及在胃癌进展的作用机制，为胃癌治疗新靶点的确定提供依据。

Gastric cancer is a highly heterogeneous malignant tumor, and CAFs is differentiated from has multiple types of cells, which is attributed to the high heterogeneity of gastric cancer. However, the degree of heterogeneity of CAFs, the regulation for CAFs heterogeneity and its effects on gastric cancer progression remain unclear. We have previously found that there were six subsets of CAFs in gastric cancer, and GPR4+CD36+CAFs subset indicated a poor prognosis for gastric cancer patients. The acidic microenvironment promoted the differentiation of GPR4+CD36+CAFs, and GPR4+CD36+CAFs presented antigen cross-presenting function. Based on the previous study, we propose the following hypotheses: There are six heterogeneous CAFs subpopulations in gastric cancer, which exhibit different relationship with the pathological characteristics and prognosis of gastric cancer patients; acidic microenvironment induces the differentiation of GPR4+CD36+CAFs through GPR4-CGMP-PKG-MEF2C pathway, and GPR4+CD36+CAFs express immune checkpoint molecules B7-H3 and CD155 to inhibit CD8+ T cell function through cross antigen presentation, which finally promote immune escape of gastric cancer. In this project, we will study the heterogeneity and clinical significance of gastric cancer CAFs, the key molecules in regulating CAFs differentiation, the regulatory mechanisms of GPR4+ CD36+CAFs and its effects on immune escape in gastric cancer. Thus, our study elucidates the heterogeneity of CAFs and its role in the progression of gastric cancer, which will provide evidence for the identification of new targets for microenvironment therapy of gastric cancer and the development of novel CAF-targeting therapies for gastric cancer.