共抑制因子CD200R诱导NK细胞功能耗竭及其HBV介导肝癌的免疫逃逸机制

The effectiveness of cancer immunotherapies targeting co-inhibitory molecules CTLA-4 and PD-1 have fully validated that reversal of tumor immune tolerance is an important new pathway for the treatment of tumor. Recently, CD200R has been demonstrated to co-inhibit NK-cell functions. A striking inhibitory effect on tumor growth and metastasis in the CD200R1-KO mice has been causally linked to the activation of NK cell. Our recent studies published in PloS Pathogen have revealed for the first time that high levels of TGF-beta was responsible for the inhibition of NK cell activating receptors and performance in the immune tolerant phase of HBV patients, which were the potential population of hepatocellular carcinoma.Thus, we hypothesize that the same inhibition and exhaustion of NK cell in the HBV+-HCC patients. We intend to enlarge the study population of HBV+-HCC with emphasizing on different disease-progressing groups, in order to further confirm whether the proinflammatory cytokines in the immune microenvironment of hepatitis and HCC are highly related to the development of HCC. Furthermore, we plan to investigate the expression of CD200R and the function of NK cells from peripheral blood and different tissue regions of HCC, the expression of CD200 (CD200R ligand) on liver parenchyma/cancer cells, as well as the regulatory effects of the key proinflammatory cytokines on the interaction of NK cell with HCC cells. This study will help to understand the mechanism of immune tolerance of NK cells induced by HCC and verify the potential value of CD200R as a novel intervention target for cancer immunotherapy.

靶向共抑制因子CTLA-4/PD-1的肿瘤免疫治疗已经充分验证了逆转肿瘤免疫耐受是重要的治疗新途径。近期发现CD200R可引起NK细胞功能耗竭，CD200R-KO小鼠NK细胞高度活化并阻滞肿瘤生长转移。我们近期发表在PloS Pathogen的结果首次显示，HBV免疫耐受期病人(肝细胞癌HCC的潜在人群)NK细胞处于耗竭状态，活化性受体明显下调；因此我们推测在HCC病人可能也伴随着NK细胞功能抑制及耗竭，我们拟对HBV相关HCC人群严格分型，探究在肝炎和肝癌免疫微环境负调细胞因子与病情的发生发展相关；同时深入研究HCC病人外周血和肝癌组织不同区域NK细胞功能与CD200R表达、肝脏实质组织/癌细胞CD200（CD200R配体）表达、以及主要负调细胞因子对以上细胞相互作用的调控效应，以了解HCC诱导NK细胞的免疫耐受机制并验证CD200R作为肿瘤免疫干预靶点的价值。

通过针对大样本量标本库中乙肝相关肝癌病人癌组织和癌旁组织的检测，发现HBV 肝癌病人癌中心组织区域中共抑制分子CD200R和NKG2A的表达水平显著高于癌旁区域。进一步发现癌组织中NK细胞活化性受体明显下调，癌中NK细胞免疫功能耗竭，是由于NKG2A显著上调所导致。肝脏内高表达NKG2A及其受体HLA-E的肝癌患者组，其总生存周期和无疾病生存周期均明显低于低表达NKG2A的患者组。我们还揭示了肝癌免疫微环境负调细胞因子IL-10与病情的发生发展密切相关；体外抗体阻断IL-10可以逆转负调细胞因子对NK细胞的负调效应，该研究工作揭示了HCC诱导NK细胞的免疫耐受机制并验证NKG2A作为肿瘤免疫干预靶点的价值（OncoImmunology，2016）。除此之外，我们还发现了一系列与肝癌患者预后相关的指标。（Immunol Lett，2016; Oncotarget，2015; J Gastroenterol Hepatol，2016）