【作者】 王志会；

【导师】 冯友梅； 白雪峰；

【作者基本信息】 华中科技大学 ， 生物化学与分子生物学， 2013， 博士

【摘要】 白介素35（IL-35）是白介素12（IL-12）家族的新成员，由p35亚基和EBI3亚基组成，受体是IL-12Rβ2和gp130。现已证明IL-35可以通过其受体发挥抗炎作用，其在多种自身免疫性疾病中的作用已有比较深入的研究，但在肿瘤方面目前为止还未见有文献报道。虽然有研究表明IL-35由调节T细胞（Treg）产生，但基因表达分析显示IL-35有着更广泛的表达分布，包括在多种肿瘤组织内的表达。首先，我们利用人体肿瘤组织进行免疫组化染色，发现在人巨型B细胞淋巴瘤、鼻咽癌、皮肤黑色素瘤和淋巴结转移性黑色素瘤中均发现有IL-35的表达。我们通过转染法将IL-35导入浆细胞瘤J558和黑色素瘤B16细胞中，并经过药物筛选得到稳转细胞株，以此研究肿瘤源性的IL-35在肿瘤免疫和肿瘤发生方面的作用。结果我们发现IL-35对肿瘤细胞在体外的生长不产生影响，但在野生型和免疫缺陷型小鼠体内对肿瘤生长有明显的促进作用。肿瘤源性的IL-35增加了CD11b+Gr1+髓源性细胞在肿瘤微环境内的聚集，并且促进肿瘤血管的生长。在正常小鼠体内，肿瘤特异性的CTL免疫应答被减弱了。IL-35不能直接抑制特异性CD8+T细胞的活性、分化以及功能。然而，经IL-35处理的肿瘤细胞上调了gp130的表达，同时降低了自身对CTL杀伤作用的敏感性。更多还原

【Abstract】 IL-35is a member of the IL-12family of cytokines consisting of IL-12p35subunitand IL-12p40-related protein subunit, EBV-induced gene3(EBI3). IL-35functionsthrough IL-35R (IL-12Rβ2and gp130) and has a potent immune suppressive activity.Studies demonstrated that IL-35involves in many autoimmune diseases, but few research ison IL-35in tumor.Although IL-35has been demonstrated to be produced by regulatory T cells, geneexpression analysis has revealed that IL-35is likely to have wider distribution includingexpression in cancer cells. In this study we have demonstrated that IL-35is produced inhuman cancer tissues such as large B cell lymphoma, nasopharyngeal carcinoma andmelanoma. In order to determine the roles of tumor-derived IL-35in tumorigenesis andtumor immunity, we generated IL-35producing plasmacytoma J558and B16melanomacells, and observed that the expression of IL-35in cancer cells does not affect their growthand survival in vitro, but stimulates tumorigenesis in both immune competent and Rag1/2deficient mice. Tumor-derived IL-35increases CD11b+Gr1+myeloid cell accumulation intumor microenvironment, and thereby promotes tumor angiogenesis. In immune competentmice, spontaneous CTL responses to tumors are diminished. IL-35does not directly inhibittumor antigen specific CD8+T cell activation, differentiation and effector functions.However, IL-35-treated cancer cells had increased expression of gp130and reducedsensitivity to CTL destruction. Thus, our study indicates novel functions of IL-35inpromoting tumor growth via enhancing myeloid cell accumulation, tumor angiogenesis andsuppression of tumor immunity.更多还原