Tim-3，逆转CAR-T细胞耗竭的可能靶点？

Morbidity and mortality of hematologic malignancies have been increasing in the recent years. Chimeric antigen receptor technology seems to be a new solution for those diseases. However, some of the patients receiving CAR-T therapy still suffered from relapse/no remission, due to CAR-T cell exhaustion. In previous work, the applicant’s team has found that immune checkpoint molecule Tim-3 was highly expressed on the CAR-T cells, therefore, clarifying the roles of Tim-3 in CAR-T therapy has important theoretical significance and practical value, which has not been reported at home and abroad. Since Tim-3 pathway was reported to induce immune tolerance, we hypothesize that abnormal high expression of Tim-3 on CAR-T cells may result in T cell exhaustion, and give rise to treatment failure, and knocking down the immune checkpoint molecule Tim-3 may optimize CAR-T therapy. To test our hypothesis, we plan to employ a series of state-of the-art strategies, including flow cytometry, cytokine detection, RNA interference, humanized NOD/SCID leukemic xenograft models, to achieve the following goals: 1) To systematically examine how Tim-3 regulates the biological activities of CAR-T cells at the cellular , molecular and animal levels; 2) To test the possibility of CAR-T therapy with immune checkpoint knockdown. Completing the current project will lay a solid foundation for the development of a novel immunotherapy.

血液系统恶性疾病发病率和死亡率逐年升高，嵌合抗原受体技术为此类患者提供了新的治疗选择，但仍有部分患者因CAR-T细胞耗竭而出现治疗后不缓解或复发。在前期研究中，申请者所在的研究组发现CAR-T细胞上免疫检查点分子Tim-3表达上升，然而其作用目前国内外均未见报道，因此明晰Tim-3在CAR-T治疗中的作用具有重要的理论意义和应用价值。基于Tim-3信号通路常介导免疫耐受，我们提出假说：CAR-T细胞异常高表达Tim-3可导致细胞耗竭，从而使部分患者治疗失败，采用Tim-3免疫调节点敲减的CAR-T细胞可优化治疗的设想。为此，本项目拟通过流式细胞术、细胞因子检测、RNA干扰、人源化NOD/SCID小鼠白血病模型等手段，从分子、细胞及动物整体水平等多层次探讨Tim-3分子对CAR-T细胞功能影响，并探讨免疫调节点敲减的CAR-T治疗的可能性，为合理设计新的免疫治疗策略提供依据。

血液系统恶性疾病发病率和死亡率逐年升高，嵌合抗原受体技术为此类患者提供了新的治疗选择，但仍有部分患者因CAR-T细胞耗竭而出现治疗后不缓解或复发。在前期研究中，申请者所在的研究组发现CAR-T细胞上免疫检查点分子Tim-3表达上升，然而其作用目前国内外均未见报道，因此明晰Tim-3在CAR-T治疗中的作用具有重要的理论意义和应用价值。基于Tim-3信号通路常介导免疫耐受，我们提出假说：CAR-T细胞异常高表达Tim-3可导致细胞耗竭，从而使部分患者治疗失败，采用Tim-3免疫调节点敲减的CAR-T细胞可优化治疗的设想。为此，本项目通过流式细胞术、细胞因子检测、RNA干扰、人源化NOD/SCID小鼠白血病模型等手段，从分子、细胞及动物整体水平等多层次探讨：1）不同培养体系对于原代T细胞的影响；2）冻存体系对于CAR-T功能的影响；3）Tim-3分子敲减的CAR-T治疗的可能性，为合理设计新的免疫治疗策略提供依据。

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