FOXO1调控肿瘤微环境中的Tregs在BCP-ALL免疫逃逸中的作用及机制研究

前体B细胞急性淋巴细胞白血病(BCP-ALL)占急性淋巴细胞白血病的80%左右，化疗相关的死亡率和复发率都很高，目前复发后有效的治疗手段很少。申请者前期研究表明：抑制FOXO1可有效杀灭体内及体外的BCP-ALL细胞；BCP-ALL患者骨髓中的调节性T细胞(Tregs)显著增多，这些Tregs具有免疫抑制功能且其功能的发挥与FOXO1活性有关。本课题将首先通过BCP-ALL转基因小鼠、DEREG转基因小鼠及NOD/SCID小鼠等来验证肿瘤微环境中Tregs对BCP-ALL免疫逃避的作用，然后通过体内体外实验阐明FOXO1是如何调控Tregs参与BCP-ALL免疫逃避的，并在人体标本中予以验证。因此，靶向抑制FOXO1还可通过抑制肿瘤微环境中Tregs来激活免疫系统对BCP-ALL的清除，本课题将为临床治疗BCP-ALL提供新的靶点依据。

Precursor B-cell acute lymphoblastic leukemia (BCP-ALL) accounts for about 80% of acute lymphoblastic leukemia, with high rates of chemotherapy-related mortality and relapse. Currently, there are few effective treatments after relapse. Our previous data have shown that FOXO1 inhibition can effectively kill BCP-ALL cells both in vitro and in vivo. There is a significant increase in regulatory T cells (Tregs) in the bone marrow of BCP-ALL patients, which have immunosuppressive functions that are related to FOXO1 activity. In this study, firstly, we will verify the role of Tregs in the tumor microenvironment on BCP-ALL immune evasion by using BCP-ALL transgenic mice, DEREG transgenic mice and NOD/SCID mice model. Subsequently, we will explore the mechanisms by which FOXO1 regulates Tregs' participation in BCP-ALL immune evasion. Finally, we will verify those findings in clinical patient samples. Therefore, targeted inhibition of FOXO1 can also clear BCP-ALL cells by activating immune system through inhibiting Tregs in the tumor microenvironment. Thus, this project will identify a new therapeutic target for the treatment of BCP-ALL.