FcγRIIb缺陷调控MDSC向免疫刺激型极化的生物学意义及其机制

髓源性抑制细胞（MDSC）在肿瘤和炎症中大量产生，其免疫抑制功能受到广泛关注，但对其分化调控机制却知之甚少。我们新近发现FcγRIIb缺陷荷瘤鼠脾脏MDSC精氨酸酶、IL-10和CD206表达下降，iNOS、TNF-α、CCR7和IFN-γR表达上调。推测FcγRIIb缺陷可能调控MDSC向免疫刺激表型极化。本项目拟明确FcγRIIb缺陷诱导哪种MDSC亚群极化，极化后MDSC表型、细胞因子分泌谱、对CD4和CD8 T细胞及Treg的功能影响；通过体外诱导及功能阻断等手段寻找诱导MDSC极化的关键因子，围绕STAT通路研究MDSC极化的分子机制；探讨FcγIIRb调控MDSC极化对疾病进展影响及临床意义。本研究首次阐明FcγRIIb对MDSC极化的调控作用，不仅可揭示FcγRIIb调控免疫应答的新机制，丰富对MDSC分化调控机制的认识，并为研制以MDSC为靶标的新型防治策略提供理论基础。

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid progenitor cells with immune suppressive function and has emerged as one of the central regulators of immune responses in cancer. Despite recent progress in MDSC biology, the mechanisms underlying MDSC differentiation remain less understood. More recently, we found that in FcγRIIb-/- tumor-bearing mice, splenic MDSC exhibited a lower arginase activity, IL-10 and CD206 expression but a higher iNOS activity, TNF-α, CCR7 and IFN-γR expression. We hypothesized that FcγRIIb deficiency may manipulate MDSC polarization from immunosuppressive to immunostimulating phenotype. In this study, we will further determine the origin, subset, phenotype and functional characteristics of MDSC from FcγRIIb-/- tumor bearing mice and dissect the underlying mechanisms for altered phenotype. Moreover, we will explore the roles of FcγRIIb-/- MDSC during tumor progression. The results obtained from this project might be helpful to better understand the mechanisms underlying MDSC polarization and the pivotal role for FcγRIIb in regulating immune response, and open novel avenues for therapeutic strategies.