乳腺癌髓源性免疫抑制细胞 (MDSCs) 通过j激活PI3K/Akt途径诱导CTLA-4+CCR6-CD62L- B细胞发挥调节样免疫功能的研究

MDSCs是一类与肿瘤免疫逃逸密切相关的髓系细胞，目前关于MDSCs对B细胞的免疫调控尚未阐明。前期结果表明乳腺癌MDSCs诱导CTLA-4+CCR6-CD62L-B细胞发挥免疫抑制作用，且诱导该B细胞中PI3K/Akt高表达。阻断PI3K/Akt能够逆转B细胞表面CTLA-4的表达并减弱B细胞的免疫抑制功能。进一步发现阻断MDSCs中非经典NF-ƙB途径能够下调自身IDO的表达，并减弱B细胞的免疫抑制作用。本课题将以BALB/C小鼠4T1乳腺癌为模型，阐明乳腺癌MDSCs通过非经典NF-ƙB途径调控IDO表达，激活CTLA-4+CCR6-CD62L-B细胞中PI3K/Akt通路，进而诱导其发挥免疫抑制功能。本项目的完成将有助于了解B细胞的免疫抑制作用，同时为抗肿瘤免疫效应机制以及肿瘤治疗新方法的研究提供一定的理论基础。

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that suppress T-cell activity in a tumor microenvironment. However, the suppressive function of MDSCs on B cells and its underlying mechanism remain unclear. Here, we successfully constructed BALB/C mice 4T1 breast cancer model. We show that the surface molecules of B cells are remolded, with molecules such as CTLA-4, CCR6 and CD62L changing prominently in the presence of MDSCs. The subset of CTLA-4+CCR6-CD62L-B cells was obviously increased in the presence of MDSCs. MDSCs emerge as vital regulators in B-cell inhibitory immune functions such as inhibition of IFN-ɣ secretion. Further detection showed that NF-ƙB and IDO in breast cancer MDSCs increased. Less translocation of RelB was associated with IDO inhibition. Analysis by western blot demonstrated that PI3K/Akt pathway was activated in CTLA-4+CCR6-CD62L-B cells. Targeting PI3K/Akt could reverse CTLA-4 expression on B cells and further attenuate CTLA-4+CCR6-CD62L-B cells′ suppression on IFN-ɣ secretion of normal T cells. Application of the inhibitor targeting IDO could block PI3K/Akt and reverse CTLA-4 expression on B cells. Our current project is aimed to identify that MDSCs can educate normal B cells and induced a novel CTLA-4+CCR6-CD62L-B cell-subset, which can exert immunosuppressive functions via PI3K/Akt pathway. The accomplishment of this project might extend our understanding of inhibitory immune functions of B cells in tumor microenvironment and might shed new light on anti-tumor immunity and immune therapy.