骨髓微环境对抗白血病中心记忆T细胞的影响和机制

正常的T细胞免疫功能在诱导白血病缓解治疗过程和预防复发中起重要作用。而髓性白血病患者常伴有抗白血病T细胞功能缺陷，其机制可能与中心记忆T细胞耗竭相关。以往研究集中在对外周血T细胞的分析，而骨髓免疫抑制微环境对抗白血病中心记忆T细胞的影响研究甚少。. 本项目拟系统研究髓性白血病（1）病人骨髓和外周血记忆T细胞表型和分布，T细胞功能耗竭程度；（2）骨髓免疫微环境组分中免疫抑制性受体（配体）表达模式；（3）通过AML人源化小鼠模型（PDX）分析不同来源和不同状态T细胞抗白血病效应的差异性及其分子机制；（4）通过受体干预等方式逆转骨髓免疫抑制微环境，探讨恢复T细胞抗白血病效应的可能。. 研究成果将有助于理解区域免疫抑制对全身性抗白血病免疫应答的作用，为探讨骨髓微环境对中心记忆T细胞所产生的影响，提高抗白血病T细胞免疫、减少复发和延长生存期提供新的免疫治疗策略。

Normal T cell immune function play a crucial role during induction therapy for leukemia remission and relapse prevention. However, anti-leukemia T cell immunodeficiency is a common feature in patients with myeloid leukemia, the mechanism might be related to central memory T cell exhaustion. Previous studies mostly focused on the change of peripheral blood T cells, little is known the influence on anti-leukemia central memory T cells by bone morrow immune suppression microenvironment. .Therefore, in this study, we aim to investigate (1) the phenotype and distribution of memory T cell, and the status of T cell exhaustion in bone marrow and peripheral T cells from patients with myeloid leukemia; (2) the expression pattern of T cell immune suppression receptors (ligends) in cells of bone marrow microenvironment component; (3) evaluation on the difference of the anti-leukemia effect between different derived and different status T cells, and it molecular mechanism by using humanized acute myeloid leukemia (AML) PDX (Patient-derived xenograft) mice model; (4) the possibility of restore of anti-leukemia effect based on reversion the status of bone marrow immune suppression by immune checkpoint blockades. .The study will be expected to better understand the influence on systemic anti-leukemia immune response by local immune suppression. Overall, the study will characterized the influence on central memory T cells by bone marrow microenvironment, and provide the novel immunotherapy strategy for enhancement the anti-leukemia effect, relapse prevention and extension survival for leukemia patients.