新型PD-L1+CD14+HLA-DR-MDSCs亚群在食管鳞状细胞癌淋巴结转移中的作用机制研究

Myeloid-derived suppressor cells (MDSCs) is a heterogeneous population of cells that expands during cancer. MDSCs has a remarkable ability to suppress T-cell responses, and play an important role in tumor immune escape. In previous studies, we found a novel subset MDSCs hallmarking with a phenotype of PD-L1+CD14+HLA-DR- in peripheral blood and tumor metastasic lymph node from patients with esophageal squamous cell carcinoma (ESCC). On this base of previous findings, we propose to investigate the biological effect of PD-L1+CD14+HLA-DR-MDSCs in lymph node metastasis and immune escape of ESCC. To this aim, we firstly plan to analyze clinical significance of the level of PD-L1+CD14+HLA-DR-MDSCs in peripheral blood and tumor drainning lymph node through clinical cases analysis. Secondly, we will investigate the functional feature of PD-L1+CD14+HLA-DR-MDSCs on T proliferation in tumor microenvironment through in vitro. Furthermore, through in vivo and in vitro experiments, we intend to assess the biological effects and molecular mechanisms of PD-L1/PD-1 signal pathway in the PD-L1+CD14+HLA-DR-MDSCs mediated immune responses of tumor antigen-specific T lymphocytes. Lastly, we plan to investigate the role of PD-L1+CD14+HLA-DR-MDSCs on lymph node metastasis through in vitro and in vivo, and analyse the biological mechanism by whole genomic gene chip. In conclusion, we aim to analyze the biological effect and mechnism of novel PD-L1+CD14+HLA-DR- MDSCs subpopulation in lymph node metastasia and immune escape of ESCC, and provide some evidence for the intervene to immune checkpoint molecule PD-L1.

髓源性抑制细胞（MDSCs）是一群来源于骨髓祖细胞的表型异质细胞群，在肿瘤患者体内异常增高，对T细胞抗肿瘤免疫具有的抑制作用，是参与肿瘤免疫逃逸的重要的抑制性免疫细胞。本项目前期工作在食管鳞状细胞癌患者外周血和肿瘤转移淋巴结中发现一群PD-L1+CD14+HLA-DR-的MDSCs新型亚群，其表达水平与疾病分期及预后相关，但确切机制尚待进一步探讨。本研究拟通过临床标本和不同水平分析，探讨食管鳞癌患者外周血和肿瘤引流淋巴结中该MDSCs亚群表达的临床意义，继而采用体内外实验，研究该MDSCs亚群的生物学特性，PD-L1/PD-1信号途径在该MDSCs亚群介导T细胞抗肿瘤免疫应答中的作用，在此基础上通过基因芯片分析该MDSCs亚群在肿瘤淋巴结转移中的关键分子或信号途径。本项目将进一步阐明这群新型MDSCs在食管鳞癌淋巴结转移和免疫逃逸中的作用，还为负性免疫卡控分子PD-L1的干预提供新的思路。

国家自然科学基金青年项目《新型PD-L1+CD14+HLA-DR-MDSCs亚群在食管鳞状细胞癌淋巴结转移中的作用机制研究（31300746）》在项目执行结束，共获得了如下研究进展：.1）发现食管癌外周血循环单核CD14+HLA-DR-/lowMDSC而非多核MDSC与食管癌患者临床进展密切相关，CD14+HLA-DR-/lowMDSC高表达PD-L1并介导了T细胞增殖和功能抑制，阻断PD-1/PD-L1信号逆转了CD14+HLA-DR−/low MDSCs对活化的自体T细胞增殖的抑制作用；且发现肿瘤转移阳性区域淋巴结中CD3+T细胞上PD-1水平显著高于未见肿瘤转移的淋巴结，提示PD-1在区域淋巴结表达与肿瘤转移状态密切相关。.2）受项目资助，项目组对肺癌免疫微环境也进行了相关研究：发现Th细胞亚群在肺癌微环境中的分布规律，并首次报道Th1high是肺癌预后差的重要指标；发现肺癌微环境中13个趋化因子配体表达与肿瘤复发转移的关系，首次报道GROαhigh、IP-10low、MIGlow可作为NSCLC病情进展指标；证实肺癌细胞表达的PD-L1抑制肿瘤相关T细胞增殖和功能，阻断PD-1/PD-L1信号逆转了T细胞增殖的抑制，并且抑制了肿瘤的生长；首次鉴定了一群以B7-H3+为特征的CD14+HLA-DR-/low的MDSC亚群，并且该群细胞可以通过IL-10途径促进Treg体外扩增，促进肿瘤进展。.总之，本项目围绕共刺激分子PD-1/PD-L1以及B7-H3，探讨了MDSC在食管癌和肺癌中的临床意义。标注基金资助发表SCI论文3篇，接受待发表论文1篇。