肿瘤诱导增高的CD4+CD25high调节性T细胞选择性下调对肿瘤免疫功能的影响及机制

In our previous study，through a novel strategy of cancer immunotherapy：selective and targeting immunomodulation， the balance of the cellular immunity can be maintained and the immunotolerance mediated by regulatory T cells is timely eliminated.But the mutual or multiple regulatory relationship among different elements of the cellular immunity and its influence on tumor immunity in the novel treatment remains unclear. The present project,through further clinical and experimental studies, aims at uncovering:(1) the immunocellular properties of tumor-induced CD4+CD25high regulatory T cells and its subsets and their function characteristics.(2)IFN-αmediated down-modulation of Foxp3 and CD25 molecules in the CD4+CD25high cells,the mechanism ,affect to its inhibitory regulatory function, and its transformation(dye, apoptosis or tranforming to other cell types).(3)the influences of CD4+CD25high down-modulation to tumor-induced immunotolerance and its mechanism and long-term maintaining balance of the cellular immunity by the selective and directed immunomodulation therapy to antitumor immunity. The study will provide fundamental data for uncovering the property and mechanism of tumor-induced immunotolerance mediated by CD4+CD25high regulatory T cells, for further investigation of the novel immunotherapeutic strategy of selective and directed immunomodulation, and for designation of novel regimens of cancer immunotherapy.

在我们前期研究中，通过"选择性定向免疫调理"新型肿瘤免疫治疗策略，成功实现了肿瘤患者细胞免疫平衡的动态维持和调节性T细胞（Treg）介导的免疫耐受的及时清除，但其中的细胞免疫各元素之间的调控规律和对肿瘤免疫的确切影响仍有待于深入研究。本研究将通过进一步的临床和体外实验研究，探讨（1）肿瘤诱导增高的CD4+CD25high细胞各亚群的免疫细胞学本质和功能特征；（2）IFN-α介导CD4+CD25high细胞Foxp3和CD25分子选择性下调的作用、机制、对该细胞抑制性调节功能影响及该细胞的转归（死亡、凋亡或转化）；（3）CD4+CD25high选择性下调对肿瘤诱导的免疫耐受的影响及机制，并进一步探讨细胞免疫平衡动态维持对肿瘤免疫功能的影响。研究结论将对揭示Treg介导肿瘤免疫耐受及其选择性调控机制、深入研究"选择性定向免疫调理"肿瘤免疫治疗新策略、新型肿瘤免疫治疗方案制定提供实验依据。

完成了783例次肿瘤患者的细胞免疫平衡分析、 379例次免疫信号表达分析、221例次肿瘤患者选择性免疫功能调理治疗。.建立并完善了CD25、Foxp3、CD28、CTLA-4、PD-1、PD-2 表达的荧光定量分析方法,除了完成课题免疫调控信号表达监控,也已经常规用于临床肿瘤免疫监控，如在临床热点肿瘤免疫领域PD-1单抗药物用于“免疫检查点”阻断肿瘤免疫治疗监控中获得了满意的结果。.明确了调节性T细胞在肿瘤免疫耐受中的作用和地位：调节性T细胞肿瘤免疫耐受调控主要发生在肿瘤局部；全身性调节性T细胞调控发生在细胞免疫高度活化的状态下，其权重在反应性和幅度上明显小于TGF-ß、IL-10、PD-1/PD-L1、CTLA-4等因素；肿瘤抗原特异性调节性T细胞作用不明显，调节性T细胞参与的肿瘤免疫耐受调控具有泛作用的特点。.优化了临床CD4+CD25high 选择性下调的方案;明确了调节性T细胞选择性调控参与癌症预防的优化方案; 明确了调节性T细胞选择性调控参与的肿瘤康复治疗的优化方案。.发表了4 篇SCI 论文; 培养了1名博士后和5 名硕士研究生或具有该领域专长的研究及技术人员。