共刺激分子B7-H3通过糖酵解途径调控结直肠癌微环境T细胞免疫应答的作用和机制

新型免疫卡控点分子B7-H3在多种实体瘤中均高表达且与预后不良相关，但其对T细胞的直接调控效果并不显著，提示其可能存在间接调控机制。项目组前期工作发现，B7-H3可以通过与Hes1结合显著促进结直肠癌细胞糖酵解并促进丙酮酸的产生；继而又发现丙酮酸可通过抑制丙酮酸脱氢酶激酶（PDHK）的活性显著抑制CD8+T细胞免疫应答。据此我们推测：B7-H3可以通过调控肿瘤细胞糖酵解进而抑制CD8+T细胞免疫应答，促进结直肠癌免疫逃逸。为验证上述假说，本项目以B7-H3为切入点，以结直肠癌为研究对象，从细胞水平、动物水平及结直肠癌组织标本出发，着重探讨该分子如何通过糖酵解调控T细胞应答的作用和机制，旨在丰富肿瘤免疫卡控点阻断治疗手段，具有良好的临床应用前景。

As a novel immune checkpoint molecule, B7-H3 is overexpressed in multiple solid tumors and is associated with poor prognosis. However, the direct regulatory effect of B7-H3 on T cells is not significant, suggesting that this molecule may regulate T cell function via indirect mechanisms. Our preliminary studies showed that B7-H3 could promote glycolysis, leading to pyruvate production by combining with Hes1. Furthermore, pyruvate regulated the CD8+ T cell cytotoxicity to tumor cells by inhibiting the activity of pyruvate dehydrogenase kinase (PDHK). Based on the previous reports and our preliminary experimental data, we hypothesis that B7-H3 inhibits the CD8+ T cell cytotoxicity and promotes the tumor immune escape by upregulating the glycolysis in colorectal cancer (CRC). To demonstrate this hypothesis, we will clarify the role and molecular mechanism of B7-H3 in regulating T cell response through regulating the glycolysis at the cellular, molecular levels and clinical tissue specimens. This project would improve the immune checkpoint blockade immunotherapy and have clinical application prospects for CRC treatment.