肿瘤微环境中脂质代谢异常促成髓样抑制细胞的分子机制

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that negatively regulate T cell immune responses. MDSCs induce tumor angiogenesis by releasing various cytokines, then promote tumor growth and metastasis. Many tumor tissues can evade immune clearance by releasing free fatty acids. However, the lipid metabolic characteristics that regulate MDSCs function remain unclear. . Our previous work indicated that compared to the saturated fatty acid, monounsaturated fatty acid increases the immune-suppressive function of MSC-2 cell line, which relies on T cell apoptosis via production of nitric oxide. In this project, we plan to detect the immunological effect of MDSCs treated with various fatty acids (saturated, monounsaturated and polyunsaturated fatty acids). We will utilize Tnfr-/- mice to set up tumor-bearing models. The proteomics and metabonomics analyses will help us to understand the mechanisms of differentiation, proliferation and immune-suppressive activity of MDSCs in tumor microenvironment which mediated by pro-inflammatory cytokines and lipid metabolism pathways. The research will provide new molecular targets of MDSCs for the clinical immunotherapy application.

髓样抑制细胞（myeloid-derived suppressor cells, MDSCs）是一群能够下调T细胞免疫功能的异质性细胞，并通过释放多种免疫效应因子诱导肿瘤血管生成，促进肿瘤细胞生长和转移。不少肿瘤组织通过释放游离脂肪酸来影响免疫功能，但是脂质代谢是否影响MDSCs的形成和功能，目前还不是十分清楚。本课题组前期研究表明，单不饱和脂肪酸相较于饱和脂肪酸显著增强MDSC细胞系MSC-2对T细胞的免疫抑制作用，这一抑制效应是依赖于NO合成诱导的T细胞凋亡。本项目拟首先在细胞水平检测不同类型脂肪酸对MDSCs形成的作用，利用已有的多种影响脂代谢的炎症因子受体敲除小鼠（例如，TNFR-/-），构建荷瘤小鼠模型，结合蛋白质组和脂肪酸代谢组学探讨肿瘤微环境中炎症因子与脂质代谢通路是如何影响MDSCs的聚集、分化和对T细胞功能的抑制作用，力图寻找合适的分子靶标能够应用于临床对肿瘤免疫的治疗。

哺乳动物免疫系统随着年龄的增加其功能逐步降低，从而增加了感染风险和自身免疫性疾病的产生，这一过程被称之为免疫衰老。老年个体的免疫系统功能降低，免疫细胞的功能随之改变并分泌产生大量的炎症因子，包括IL6，CRP，IL-1b和TNFa等。其中，我们关注到老龄化过程不仅影响髓源抑制细胞（myeloid-derived suppressor cells, MDSCs）在外周的聚集，还会对其自身的免疫代谢产生影响，使其脂质积累和代谢发生改变。这个过程很大程度上是由MDSCs表面的TNFR2而非TNFR1所介导的。在本研究中，我们首先发现老龄化MDSCs在炎症微环境中更偏好利用脂肪酸代谢维持其较强的免疫抑制功能，这与细胞表面TNFR2对脂质代谢的调控密切相关。我们分别利用TNFR1-/-和TNFR2-/-小鼠研究了不同基因型缺陷MDSCs的免疫代谢模式，进而证明TNFR2通过维持MDSCs在炎症环境中的高水平脂质积累，从而赋予其在免疫衰老过程中对淋巴细胞的抑制活性。最后，我们希望能够通过外源干扰老龄MDSCs中脂滴的生成，明显改善老龄小鼠的免疫功能，进一步为临床靶向治疗提供新的依据。