基于免疫抑制性受体双重调控逆转T细胞耗竭而增强抗AML作用及机制研究

T细胞耗竭制约了急性髓性白血病（AML）免疫治疗效果。逆转T细胞耗竭是改善疗效的重要途径。我们前期发现AML病人T细胞呈PD-1+/TIM-3+CD57+等耗竭表型；高表达PD-L1和溴结构域蛋白4（BRD4）的AML总生存期明显降低；BRD4抑制剂JQ1可同时下调T细胞的PD-1及TIM-3和AML细胞的PD-L1表达。因此推测：靶向抑制BRT4有可能发挥调控T细胞耗竭和抑制AML细胞增殖双重作用。故本课题拟研究①JQ1逆转AML病人T细胞耗竭表型和重塑T细胞功能及分子机制；②JQ1下调PD-L1/TIM-3表达和抑制AML细胞增殖特点；③利用sPD-L1诱导人CD8+T细胞耗竭和anti-GD2 CAR T细胞自发耗竭模型（HA-28z）评估JQ1抑制其耗竭后的抗AML作用；④利用AML小鼠模型评价JQ1体内重塑抗AML作用。从而明确靶向抑制BRD4作为双重打击而抗AML的免疫治疗效应

T cell exhaustion limits the immunotherapy effect in patients with acute myeloid leukemia (AML). Reversion of T cell exhaustion is the important approach for improving the effect. Our previous findings showed that T cells expressed PD-1+/TIM-3+CD57+ exhausted phenotype in AML patients, higher co-expression of PD-L1 and Bromodomain-containing protein 4 (Brd4) related to poor overall survival, BRD4 inhibitor JQ1 can down-regulate both PD-1 and TIM-3 expression in T cells and PD-L1 expression in AML cells. Thus, we speculate that targeting inhibition of BRD4 may have double effects on reversing T cell exhaustion and inhibiting proliferation of AML cells. Therefore, in this study, we will investigate: ① whether JQ1 reverses T cell exhaustion and rebuilds T cell function, and characterize its mechanism, ② whether JQ1 down-regulates PD-L1/TIM-3 expression and inhibits proliferation in AML cells, ③ to evaluate the anti-AML effect by sPD-L1 inducted human CD8+ T cell exhaustion and spontaneous exhaustion model anti-GD2-CAR-T cells after exhaustion reversing by JQ1 treatment, ④ to evaluate the recovering anti-AML effect in vivo in AML mouse model after JQ1 treatment. Finally, the study is expected to characterize the possibility of double impact of anti-AML immunotherapy by target BRD4 inhibition.