目前非组蛋白甲基化修饰调控效应及其机制受广泛关注，胞内信号分子赖氨酸甲基化在其活化和调控中发挥重要作用。DNA去甲基化药物如地西他滨等已证实具有抗肿瘤临床疗效，但以往多关注药物对肿瘤细胞的调节而对机体免疫细胞的直接作用尚不清楚。在本团队低剂量去甲基化药物治疗实体瘤的临床试验中，我们发现低剂量地西他滨能够增强T细胞活化、增殖及抗肿瘤杀伤活性，可能通过促进T细胞IκBα降解而激活NF-κB信号通路，且观察到IκBα蛋白甲基化程度降低。据此，我们开创性提出地西他滨享有“免疫增效”效应，且具有“调控非组蛋白甲基化”全新作用机理。本课题拟研究地西他滨对不同T细胞亚群及肿瘤细胞差异调控效应，进而解析地西他滨对IκBα蛋白甲基化及NF-κB活化的调控作用机制，阐明低剂量地西他滨抗肿瘤免疫效应及其对胞内信号分子甲基化调控新机制，并从机体免疫功能角度挖掘地西他滨表观治疗临床反应性预测指标，实现肿瘤精准治疗。

The effects and mechanism of non-histone protein methylation attracts attention nowadays. Recent studies indicated that protein lysine methylation regulates the activation of the intracellular molecules. The DNA demethylating agents such as decitabine have displayed significant clinical responses in cancer treatment. However, the previous studies mainly focused on the regulation of tumor cells while the direct function of these drugs on the host immunocytes was still unclear. Based on the observations from our clinical trials of “low dose decitabine based therapy in patients with refractory and/or chemotherapy resistant solid tumors”, we demonstrated that low-dose decitabine promoted the activation, proliferation and cytolytic capacity of CTL cells probably by inducing NF-κB activation through the downregulation of IκBα. Moreover, we observed the IκBα methylation level was decreased using the pan-lysine methylation antibody. Thus, we supposed that decitabine could be the novel “immunosensitizer” and possess the capacity to “regulate the non-histone protein methylation”. In this project, we intend to investigate the different effects of low-dose decitabine in controlling the proliferation between distinct T lymphocyte subsets and tumor cells; analyze the regulation mechanism of IκBα protein methylation and NF-κB activation following low dose decitabine treatment; clarify the novel role of decitabine in non-histone protein methylation regulation and the detailed anti-tumor T cell immunity of low-dose decitabine in solid tumor treatment; and explore the anti-tumor immunity-related biomarkers of clinical reactivity in response to this epigenetic therapy, to eventually realize the precision medicine.