PUFA重编程MDSC脂质代谢的分子机制及其在肿瘤免疫逃逸中的作用研究

Myeloid-derived suppressor cells (MDSCs) present in most individuals with cancer inhibit antitumor immunity resulting in tumor escape and represent a major limitation in the development of different forms of immunotherapy. In our previous studies, we had confirmed that Polyunsaturated fatty acids (PUFAs) directly changed the lipid metabolism of MDSCs, and then promoted the accumulation and activation of MDSCs by STAT3 signaling pathway resulting in tumor escape. However, the molecular mechanism of PUFAs regulation of lipid metabolism of MDSCs and its effect on tumor escape remained unclear. We recently found that the G protein-coupled receptor GPR120 on the cell membrane and TIPE3, the transfer protein of lipid second messengers,which both of two had some relation with lipid metabolism,were involved in the process.This suggested that PUFAs caused the occurrence of tumor immune escape by GPR120, TIPE3 lipid metabolic pathways . Therefore,basis on these results, this project will systematically use in vivo and in vitro tumor models and intend to focus on studying GPR120 and TIPE3-related signaling pathways in order to clarify the mechanism of tumor escape induced by MDSC's abnormal lipid metabolism. In all, this project will lay a new foundation for the therapeutic potential of targeting MDSC for cancer immunotherapy.

髓系来源的抑制性细胞（MDSCs）抑制抗肿瘤免疫反应，导致肿瘤免疫逃逸发生，这是临床上肿瘤免疫治疗的最大限制因素。我们前期研究表明，多不饱和脂肪酸（PUFAs）影响MDSCs脂质代谢水平，并通过 STAT3 信号通路促进MDSCs的聚集和活化，导致肿瘤免疫逃逸的发生。然而，PUFAs调控MDSCs细胞内脂质代谢的分子机制及其对肿瘤免疫逃逸发生的作用还不清楚。我们又发现，细胞膜上与脂质代谢相关的G蛋白质偶联受体GPR120 和脂质第二信使转运蛋白TIPE3都参与到该过程，这提示PUFAs可能通过 GPR120、TIPE3等脂质代谢通路来引起肿瘤免疫逃逸的发生。据此，本项目拟系统地使用体内外肿瘤模型，围绕MDSCs细胞内GPR120、TIPE3等脂质代谢信号通路展开研究，以期阐明 MDSC脂质代谢异常引起肿瘤免疫逃逸的机制。本项目将对临床上以MDSCs为靶点的肿瘤免疫治疗产生重要的指导意义。

髓系来源的抑制性细胞（MDSCs）是一种“极化”的髓系细胞，能够通过抑制抗肿瘤免疫反应来有效地促进肿瘤发生。目前髓系细胞在肿瘤发生过程中是如何获得促肿瘤特性还不清楚。我们的最新研究表明，与脂质第二信使转运蛋白TIPE3在分子结构和氨基酸组成上高度相似的同一家族的另一分子极性蛋白TIPE2（肿瘤坏死因子-α–诱导蛋白8-2）介导MDSCs细胞功能性极化从而调控其促肿瘤或抗肿瘤特性。肿瘤细胞通过活性氧（ROS）诱导Gr1+CD11b+细胞上调表达TIPE2。TIPE2反过来增加促肿瘤介质如CCAAT/增强子结合蛋白β而抑制抗肿瘤因子的表达。因此，TIPE2缺陷小鼠肿瘤的生长受到明显抑制，并且过继转移TIPE2缺陷的MDSCs也明显抑制肿瘤的生长。药物阻断ROS不仅抑制了MDSCs细胞内TIPE2的表达而且减少了小鼠肿瘤的生长。这些结果表明，TIPE2在MDSCs功能性极化中起着关键的作用，是肿瘤免疫治疗的新靶点。