Toll样受体激动剂促进γδ T细胞抗骨肉瘤细胞

发布时间：2018-04-22 15:12

本文选题：γδ + T细胞　；参考：《浙江大学》2017年硕士论文

【摘要】：骨肉瘤是发病率最高的骨恶性肿瘤,具有易复发及肺转移率高的特点。上个世纪八十年代后,通过手术联合化疗的方案,显著提高了疗效,使五年以上的预期寿命达到了接近70%,但是近三十年来却一直没有进一步改善。特别是复发的或者存在肺转移的骨肉瘤,目前的治疗手段疗效极差。另外,高剂量的化疗药如甲氨蝶呤和阿霉素等,存在很大的副作用。因此,急需新型安全高效的治疗手段治疗骨肉瘤。免疫治疗是治疗骨肉瘤的综合治疗手段之一,被认为是继手术和化疗之后的第三类治疗手段。近年来,关于过继T细胞抗肿瘤的研究得到了越来越大的重视。其中,作为肿瘤免疫治疗的重要组成部分,γδ T细胞抗肿瘤的作用已成为热点。本课题组已证实γδ T细胞对骨肉瘤细胞能产生细胞毒性,但是γδ T细胞对肿瘤细胞识别能力不足,以及肿瘤微环境中存在的如Treg细胞具有免疫抑制作用,限制了 γδ T细胞免疫治疗的临床应用。随着模式识别受体概念的提出,具有较强免疫调节功能的Toll样受体(toll-likereceptor,TLR)是近些年来免疫学的重大进展。本课题探究TLR激动剂对γδ T细胞杀伤骨肉瘤的促进作用及其机制,为骨肉瘤患者过继免疫治疗提供科学依据。本次研究分为两部分。一、获取健康志愿者的外周血单核细胞,通过ZOL和IL-2联合刺激以扩增获得高纯度的γδ T细胞。二、在第一部分的基础上,探索TLR3激动剂促进γδ T细胞杀伤骨肉瘤细胞的能力和机制。结果发现TLR3激动剂具与γδ T细胞联合具有协同增强抗骨肉瘤细胞的能力。进一步研究显示TLR3激动剂预处理骨肉瘤细胞后,会引起骨肉瘤细胞表面CD54的表达升高,引起γδ T细胞CD107a表达水平提高,并刺激γδ T细胞分泌炎症因子,从而产生协同促进γδ T细胞抗骨肉瘤的作用。
[Abstract]:Osteosarcoma is the highest incidence of bone malignant tumor, with the characteristics of easy recurrence and high rate of lung metastasis. After the eighties of the last century, the curative effect was significantly improved by the combination of surgery and chemotherapy, and the life expectancy of more than five years reached nearly 70%, but no further improvement has been made in the past 30 years. In particular, recurrent or pulmonary metastases of osteosarcoma, the current treatment is extremely ineffective. In addition, high-dose chemotherapy drugs such as methotrexate and adriamycin have great side effects. Therefore, a new safe and effective treatment for osteosarcoma is urgently needed. Immunotherapy is one of the comprehensive treatments for osteosarcoma and is considered to be the third treatment after surgery and chemotherapy. In recent years, more and more attention has been paid to the study of adoptive T-cell anti-tumor. Among them, as an important part of tumor immunotherapy, 纬未 T cell anti-tumor effect has become a hot spot. Our team has confirmed that 纬未 T cells can produce cytotoxicity to osteosarcoma cells, but 纬未 T cells have insufficient ability to recognize tumor cells, and the presence of Treg cells in tumor microenvironment has immunosuppressive effect. It limits the clinical application of 纬未 T cell immunotherapy. With the development of the concept of pattern recognition receptor, Toll like receptor with strong immunomodulatory function is an important progress in immunology in recent years. The aim of this study was to investigate the promoting effect of TLR agonist on 纬未 T cell killing osteosarcoma and its mechanism, and to provide scientific basis for adoptive immunotherapy of osteosarcoma patients. This study is divided into two parts. Firstly, the peripheral blood monocytes of healthy volunteers were obtained, and the high purity 纬未 T cells were obtained by ZOL and IL-2 stimulation. Secondly, on the basis of the first part, the ability and mechanism of TLR3 agonist to promote 纬未 T cells killing osteosarcoma cells were explored. The results showed that TLR3 agonist combined with 纬未 T cells had the ability of synergistic enhancement of osteosarcoma cells. Further studies showed that pretreatment of osteosarcoma cells with TLR3 agonists increased the expression of CD54 on the surface of osteosarcoma cells, increased the CD107a expression of 纬未 T cells, and stimulated the secretion of inflammatory factors by 纬未 T cells. Thus, the synergistic effect of 纬未 T cells on osteosarcoma was produced.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R738.1

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