中国北方人群肺癌患者Cancer/Testis抗原表达谱绘制表位鉴定及功能性抗原特异性CTL制备研究

Lung cancer is leading cause of cancer mortality in China and the accidents continue increase. Thus, it is very needed to develop novel effective therapy methods, especially for the advanced patients who resisted to conventional treatment. Antigen specific T cell therapy has show unique potential advantage for the advanced cancer patients, and some patients even show long term immunoprotection and release of disease. However, there is little report about the antigen specific T cell therapy for lung cancer patients. The main reason might due to insufficient antigen target information in lung cancer. Cancer/Testis antigen (CTA) is the idea antigen target for the T cell therapy. However, there are no detailed reports for the CTA expression frequency in lung cancer patients among Chinese population. Thus, in the present study, base on our previous studies, we plan to analysis CTA expression frequency in lung cancer patients distributed in the North of China with large sample size, and draw the CTA expression profile for the first time. According to the 10 typical CTA expression profile analysis, we will define the optimized CTA combination. And then, the correlated T cell epitope will be identified according to the high frequency of HLA allele in the population of North of China. The epitope specific functional T cells will also be prepared, and the in vivo anti-tumor immunoresponse will be investigated through the SCID mouse model. If this project can be successfully carried out, it will establish excellent foundation for the development of T cell therapy for the advanced lung cancer patients distributed in North of China. This study will also provide important reference to the lung cancer patients in the South of China population. In summary, our finding from this study will significantly improve the quality of life of lung cancer patients and prolong their survival, and has broad clinical application prospect.

肺癌持续高发，传统治疗失败的患者仍迫切需要新的有效治疗手段。抗原特异性T细胞免疫治疗对于中晚期癌症患者显示出独特优势，甚至可长期治愈。但目前肺癌患者由于缺乏明确的抗原靶，导致肺癌T细胞免疫治疗尚属空白。Cancer/Testis抗原（CTA）是T细胞免疫治疗一个最理想的靶标，但中国人群表达目前尚不明确。本项目首次拟在独有的前期工作的基础上，开展大样本北方人群肺癌患者表达谱绘制，通过筛选10个经典CTA表达频次分析，应用生物信息技术确定优选CTA组合，结合北方人群HLA等位基因频次，鉴定相应的T细胞表位，并制备功能性抗原特异性CTL，进一步通过SCID鼠模型体内验证特异性T细胞的肿瘤杀伤功能。本项目如能成功实施，可为将来针对我国北方人群中晚期肺癌患者开展T细胞免疫治疗奠定极好的理论及实践基础，并为南方人群的进一步筛选提供重要借鉴，明显提高肺癌患者生存质量并延长生存周期，具有广阔临床应用前景。

肺癌发病率与死亡率高居不下，传统治疗失败的患者迫切需要新的有效治疗手段。抗原特异性T细胞免疫治疗对于滑膜肉瘤和恶黑等实体瘤显示出独特优势，甚至可长期治愈。但目前肺癌由于缺乏明确的抗原靶，导致肺癌特异性T细胞免疫治疗尚属空白。Cancer/Testis抗原（CTA）是T细胞免疫治疗一个最理想的靶标，但中国人群表达目前尚不明确。本项目首次在独有前期工作的基础上，通过200例北方人群肺腺癌及鳞癌患者手术标本绘制了北方人群的CTA表达谱，通过筛选10个经典CTA表达频次分析，应用生物信息技术确定出了不同临床病理特征的患者的优选CTA组合，大多数CTA呈现共表达,只有15.0%非小细胞肺癌病例没有表达任何CTA。200例患者至少表达1,2,3,4,5个CTA频率是85.0%,74.5%,65.0%,52.5%和43.5%。其中ADC患者为87.0%,80.0 %,80.0%,60.0%,53.0%,鳞状细胞癌患者为83.0%,69.0%,59.0%,45.0%,45.0%。最好的2、3和4 CTA组合为MAGEA1 + MAGEA10 MAGEA1 + MAGEA10 + CTAG1A / B和MAGEA1 + MAGEA10 + CTAG1A / B + VCX1(或MAGEA1 + MAGEA10 + MAGEB2 + CTAG1A / B),可覆盖72.0%、72.0%和76.5%肺癌样本。另外，我们也构建了mRNA的表达谱与蛋白表达谱进行进一步分析。进而结合北方人群HLA等位基因频次，鉴定人VCX3A HLA-A3的T细胞表位，并制备了功能性抗原特异性CTL。从体外和体内验证特异性T细胞肿瘤杀伤功能。本项目完成的基础研究为针对我国北方人群中晚期肺癌患者开展T细胞免疫治疗I期研究奠定良好基础，并为南方人群研究提供重要借鉴，为提高肺癌患者生存质量并延长生存周期提供更多治疗手段。