结肠癌ABHD5 缺失抑制EZH2活性促进效应T细胞瘤内趋化浸润的作用及机制研究

Infiltration of tumors with effector T cells is positively associated with therapeutic efficacy of immunotherapy. However, the mechanisms underlying effector T cell trafficking to the tumor microenvironment remain poorly understood. We have previously identified a lipolytic factor, ABHD5, functions as a tumor suppressor gene in colorectal cancer, but whether it is involved in regulating tumor immunoreactivity remains unknown. Our recent study have found that the H3K27m3 histone methylation is significantly suppressed in ABHD5 deficient colorectal cancer cells accompanied with an increased production of Th1-type chemokines CXCL9/CXCL10, the mediators of effector T cell trafficking. Our further work found that ABHD5 deficiency enhances the stability and nucleus translocation of CDK1, as well as CDK1-induced phosphorylation of histone methyltransferase EZH2. Based on these evidence, the present project plan to explore how ABHD5 deficiency induces effector T cell trafficking to the tumor microenvironment of colorectal cancer via regulating CDK1-induced phosphorylation and inactivation of EZH2. This study aim to reveal the molecular mechanism underlying the effect of ABHD5 in controlling tumor immunoreactivity. Therefore, ABHD5 may be derived as a biomarker predicting the efficacy of current cancer immunotherapies, and targeting ABHD5-CDK1-EZH2 axis may have significant implications for improving the efficacy of effector T cell-mediated immunity and the response to immunotherapies.

肿瘤中效应T细胞数量稀少是制约其对免疫治疗反应的重要瓶颈，但调控T细胞瘤内趋化的机制不清。我们前期证实ABHD5在结肠癌中发挥重要的抑癌基因作用，但其是否参与调控肿瘤免疫尚不清楚。我们新近研究发现，结肠癌ABHD5缺失促进瘤内抗肿瘤T细胞趋化浸润，且提高肿瘤对PD-L1抗体治疗的反应性。进一步研究表明，ABHD5影响CDK1对EZH2的磷酸化而调控组蛋白H3K27m3甲基化水平及下游Th1趋化因子CXCL9/10表达。因此，本项目拟在前期研究基础上，利用肠道特异性ABHD5敲除及转基因APCmin/+小鼠、ABHD5高低表达的结肠癌细胞及免疫、肿瘤双人源化PDX小鼠模型，探讨结肠癌细胞ABHD5缺失抑制CDK1泛素化而促进其介导的EZH2磷酸化，进而抑制EZH2相关组蛋白甲基化而上调CXCL9/10表达，导致肿瘤趋化效应T细胞能力增强的作用及机制，揭示ABHD5对结肠癌免疫微环境的影响，以期为结肠癌免疫治疗寻找到新的疗效预测标志物及增效靶点。

抑制性肿瘤免疫微环境、肿瘤新抗原及肿瘤细胞突变等是影响肿瘤恶性进展及免疫治疗的重要驱动事件。结肠癌肿瘤微环境中效应CD8+T细胞数量稀少且功能失活是胰腺癌抑制性免疫微环境的主要特征，但其受何种因素调控尚不清楚。课题组前期证实ABHD5在结肠癌中发挥重要的抑癌基因作用，但其是否参与肿瘤免疫的调控尚不清楚。本研究发现结肠癌ABHD5缺失抑制肿瘤免疫微环境，瘤内抗肿瘤T细胞趋化增多， ABHD5可以降低肿瘤细胞表面PD-L1表达，影响CD8细胞的功能，肿瘤免疫逃逸；促进肿瘤发生发展并影响对PD-1/PD-L1抗体治疗的反应性。深入研究证实ABHD5影响CDK1对EZH2的磷酸化而调控组蛋白H3K27m3甲基化水平及下游Th1趋化因子CXCL9/10表达，同时ABHD5促进PD-L1溶酶体降解进而影响瘤内抗肿瘤T细胞功能。这一研究不仅ABHD5对结肠癌免疫微环境的影响，以期为结肠癌免疫治疗寻找到新的疗效预测标志物及增效靶点.