γδ T细胞过继免疫治疗晚期原发性肝细胞肝癌和复发或难治性非霍奇金淋巴瘤的最佳适应症的组合分子标志研究

肿瘤是严重危害人类健康的重大疾病，γδ T细胞在体内外对多种肿瘤细胞系有明显的细胞毒活性，在肿瘤过继免疫治疗中具有明显的优势。γδ T细胞过继免疫治疗最佳适应症研究将大大提高其临床应用疗效。.本研究开展专利技术体外扩增的自体γδT细胞过继免疫治疗晚期乙肝相关肝细胞肝癌和复发/难治性非霍奇金淋巴瘤的临床试验，评估其安全性和有效性；并在此基础上全面系统研究以γδT细胞识别的肿瘤相关应激异位蛋白表达情况为重点，综合考虑肿瘤突变负荷和肿瘤微环境中免疫细胞浸润情况，以及肿瘤微环境、外周血γδT细胞表型、功能及CDR3免疫组库的特征的影响γδT细胞过继免疫治疗效果的分子标记物；并对这些分子标记物在实体肿瘤和血液肿瘤中的异同进行比较，总结γδT细胞肿瘤过继免疫治疗最佳适应症的一般及特殊规律。实验结果将为人们深入了解γδT细胞的抗肿瘤机制，进一步提高γδT细胞过继免疫治疗临床试验疗效奠定基础。

Tumor is a major disease that seriously endangers human health. In recent years, although the local treatment has been improved, it still cannot solve the recurrence and metastasis of tumor. Gamma-delta T cells are a unique subset of T cells. In a MHC non-restrictive manner, it has obvious cytotoxic activity in vitro and in vivo against a variety of cancer cell lines and advantages in adoptive tumor immunotherapy..In this study, we used patented technology to amplify autologous gamma-delta T cells for adoptive reinfusion in the treatment of advanced hepatitis B-related hepatocellular carcinoma (solid tumors) and recurrent/refractory non-Hodgkin lymphoma (hematological tumors). On one hand, the safety and efficacy were observed to accumulate data for large-scale clinical application of adoptive immunotherapy with gamma-delta T cells. On the other hand, on the basis of clinical trials, patients with significant therapeutic effects on adoptive immunotherapy of gamma-delta T cells were selected. The expression of 14 gamma-delta T cell-recognized tumor-related stress antigens(including ectopic expressed antigens on tumor cells), was systematically and comprehensively studied, taking into account the tumor mutation burden and the tumor infiltration lymphocytes in tumor microenvironment, including the number, location and the activation status of gamma-delta T cells, as well as the characteristics of the gamma-delta T cell receptor complementarity determining region 3 repertoire, to explore molecular markers for predicting the therapeutic effect of adoptive immunotherapy of gamma-delta T cells. The results of best indications for gamma-delta T cell immunotherapy, would lay a foundation for further clinical trials, guiding and improving the therapeutic effect of adoptive immunotherapy of gamma-delta T cells.