肿瘤胆固醇代谢物介导的免疫逃逸机制研究

肿瘤微环境中T细胞的功能往往被抑制而导致肿瘤的免疫逃逸。目前已知的PD1和CTLA4等免疫检查点通路是肿瘤免疫逃逸的重要机制，然而仍有其它重要机制还未被揭示。T细胞代谢对其效应功能至关重要，我们前期发现调控胆固醇代谢可以提高T细胞的抗肿瘤活性（Nature 2016，通讯作者）。本项目将以肠癌为模型，研究肿瘤细胞如何分泌特异性的胆固醇代谢物来影响T细胞胆固醇代谢从而实现免疫逃逸的分子机制，并发展新的干预方法来逆转这个过程。我们将首先利用动物模型和临床样品分析肿瘤微环境中T细胞的胆固醇代谢紊乱现象；利用脂质组学技术鉴定肠癌组织中异常富集的胆固醇代谢物，并研究其对T细胞胆固醇代谢的调控机制；随后鉴定产生这些代谢物的关键酶并研究其对肿瘤免疫逃逸的贡献；最后分别发展针对肿瘤细胞和T细胞的干预方法。本项目的实施将提供新的肿瘤免疫逃逸机制，并且为发展基于代谢干预的肿瘤免疫治疗方法提供新思路。

T cell function is often suppressed in the tumor microenvironment by various mechanisms such as the well-known immune checkpoint pathway. However, other immune evasion mechanisms still need to be carefully investigated to lead to novel therapies. Our earlier work demonstrates the importance of T-cell cholesterol metabolism in antitumor immunity (Yang et al. 2016, Nature, corresponding author). Here we propose to use colorectal cancer as a model to study how tumor cells use cholesterol metabolites to cause immune evasion. We will firstly use animal models and clinical samples to study the cholesterol metabolic feature of tumor-infiltrating T cell subsets. Lipidomics will then be applied to identify the abnormally enriched cholesterol metabolites in the tumor microenvironment. Mechanistic studies will be performed to understand how these metabolites interfere with T-cell cholesterol metabolism. We will also identify the key enzyme(s) in tumor cells responsible for the abnormal production of tumor-specific cholesterol metabolites and study their direct contribution to immune evasion. Finally, we will develop new interference approaches to either block the production of these metabolites by tumor cells or enhance the resistance capability of T cells. This project will shed new light on understanding immune evasion and can provide new knowledge for developing next-generation cancer immunotherapy.