FcγRIIb缺陷调控MDSC向免疫刺激型极化的生物学意义及其机制

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.

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。

MDSC在肿瘤中大量产生，其免疫抑制功能受到广泛关注，但其分化及调控机制尚不十分清楚。本项目利用FcγRIIb-/-小鼠构建B16F10和3LL移植瘤模型，发现FcγRIIb-/-小鼠脾脏中MDSC比例增高，以PMN-MDSC的增高为主。与WT小鼠脾脏MDSC亚群相比，FcγRIIb-/-小鼠脾脏MDSC亚群分泌抑制性细胞因子水平下降而分泌TNF-ɑ的水平增高，对CD4＋T细胞增殖的抑制作用减弱，诱导Treg分化的能力下降。过继回输实验发现与WT MDSC相比，FcγRIIb-/- MDSC亚群促进小鼠肿瘤生长的能力下降。与WT的骨髓细胞相比，FcγRIIb-/-骨髓细胞在体外用GM-CSF刺激后，诱导产生的MDSC比例和数量增多且TNF-ɑ分泌水平增高。进一步研究发现，FcγRIIb-/-MDSC的免疫抑制功能下降与STAT3和STAT6的活化下降有关。人外周血MDSC表面FcγRIIb的表达量的增高与肺癌的TNM分期、转移和浸润明显相关。本研究所得的结果不仅可揭示FcγRIIb参与肿瘤发生发展的新机制，丰富对MDSC可塑性的认识，更可为研制以MDSC为靶标的新型防治策略提供理论基础。