EZH2通过糖代谢调控肿瘤微环境中Treg细胞免疫调节功能的机制研究

Regulatory T cells (Treg) contribute to impaired tumor immunotherapy by suppressing antitumor immunity of tumor-associated antigen-specific T cells. EZH2 mediates gene transcriptional repression by epigenetic regulation via methyltransferase activity. We previously reported that EZH2 participated in the regulation of glycolysis, polyfunctionality and survival of human effector T cells and was correlated with T cell antitumor immunity. The roles of EZH2 in human Treg need to be elucidated. Our preliminary data showed human Treg expressed high level of EZH2, which was correlated with proliferation, apoptosis, immunomodulation and glycolysis. We also explored the possible underlying molecular mechanism. We hypothesize that EZH2 expression of Treg is elevated by tumor microenvironment, contributing to inhibiton of PHD2. Consequently, PHD2-induced hydroxylation and degradation of HIF-1α is rescued, leading to elevated glycolysis of Treg by activating GLUT-1 pathway, which contributes to the regulation of proliferation, apoptosis, cytokine production and immunomodulation of Treg. This project aims to explore the mechanism of EZH2-mediated regulation of Treg immunomodulation and figure out a novel idea and therapeutic method for colorectal cancer.

Treg细胞能够抑制肿瘤抗原特异性T细胞的抗肿瘤免疫功能，是肿瘤免疫治疗的一个主要障碍。EZH2 具有甲基转移酶活性，通过表观遗传调控抑制基因的转录。申请者在青年基金的研究中发现EZH2参与调控人效应T细胞的糖代谢、多功能性和生存，与T细胞的抗肿瘤免疫功能密切相关。但EZH2与人Treg的关系仍有待阐明。我们预实验发现Treg细胞高表达EZH2，并且EZH2与Treg细胞的增殖、凋亡、免疫调节功能和糖代谢相关，并进一步发现了可能的分子机制。本课题假设肿瘤微环境影响人Treg细胞的EZH2表达，进而抑制PHD2的转录，导致HIF-1α羟化降解减少，进而通过GLUT-1信号通路，调节Treg细胞的糖代谢水平，从而影响Treg细胞的增殖、凋亡、细胞因子分泌及免疫调节功能。本课题拟探索出EZH2调控Treg细胞免疫调节功能的机制，为结直肠癌的免疫治疗提供一种新思路和新途径。

结直肠癌标本中的Treg的EZH2表达水平明显高于健康受试者外周血中的Treg的EZH2表达， EZH2调控Treg细胞的增殖和凋亡，以及Treg细胞分泌抑制性细胞因子IL-10和TGF-β的能力。同时发现人结直肠癌组织中Treg细胞的H3K27me3表达水平明显高于健康受试者外周血中的Treg细胞。抑制CDK4/6后肿瘤生长明显变慢，并且肿瘤中T淋巴细胞的浸润明显增加，而T淋巴细胞的失能明显缓解，并且T淋巴细胞的效应功能明显增加。同时肿瘤中抑制性免疫细胞的浸润明显减少，包括调节性T细胞和抑制性巨噬细胞。CDK4/6抑制剂在与PD-1抗体、Gemcitabine/Abraxane联合处理后可以明显提高后者的免疫治疗效果。本研究有助于通过调控Treg细胞的免疫抑制功能以及T细胞的抗肿瘤免疫功能，为肿瘤免疫治疗提供了一种新的思路。