Tc17细胞促进ALDH1阳性人肾癌干细胞募集髓系来源的抑制性细胞诱导免疫逃逸的机制研究

Cancer stem cells（CSCs）have been shown to play an important role in tumor recurrence and metastases. Immune escape is one of the critical hurdles that impede effectiveness of cancer immunotherapy. The study was based on success of directly xenografting human kidney tumors into NOD/SCID IL-2rg-/- mice subcutaneously. In combination of taking experiments in vitro and in vivo, we were trying to isolate and identify CSCs of human renal cell carcinoma using ALDEFLUOR staining assay in order to reveal the key roles that CSCs played in the initiation, progression, metastases and recurrence of human renal cell carcinoma. Furthermore,based on our previous finding that tumor-infiltrating Tc17 cells was positively correlated with the frequency of aldehyde dehydrogenase 1 positive human renal cell carcinoma stem cells and myeloid-derived suppressor cells ,we sought to explore mechanisms of Tc17 cells enhancing recruitment of myeloid-derived suppressor cells by Aldehyde dehydrogenase 1 positive human renal cell carcinoma stem cells to promote immune evasion so as to find new targets of cancer immunotherapy targeted on CSCs of human renal cell carcinoma.

肿瘤干细胞是肿瘤复发和转移的关键。肿瘤免疫逃逸是制约肿瘤免疫治疗疗效提高的主要因素之一。本课题以申请者前期建立的人新鲜肾癌组织NOD/SCID IL-2rg-/-(NSG)小鼠移植瘤为基础，结合临床、体外和动物实验，采用ALDEFLUOR染色的方法分离和鉴定人肾癌干细胞。基于前期研究发现肾癌组织Tc17细胞水平与ALDH1阳性细胞和髓系来源的抑制性细胞比例呈正相关，进一步探讨Tc17细胞促进ALDH1阳性肾癌干细胞募集髓系来源的抑制性细胞诱导免疫逃逸的机制,以揭示肾癌干细胞在肾癌发生、发展、转移、复发及免疫逃逸中发挥的关键作用，为靶向肾癌干细胞的肿瘤免疫治疗提供新的理论基础和靶点。

肿瘤干细胞是肿瘤复发和转移的关键。肿瘤免疫逃逸是制约肿瘤免疫治疗疗效提高的主要因素之一。本课题以申请者前期建立的人新鲜肾癌组织NOD/SCID IL-2rg-/-(NSG)小鼠移植瘤为基础，结合临床、体外和动物实验，采用ALDEFLUOR染色的方法分离和鉴定人肾癌干细胞，并进一步探讨Tc17细胞促进肾癌干细胞募集髓系来源的抑制性细胞诱导免疫逃逸的机制。本研究发现：1.本研究组首次建立8例人肾癌新鲜组织NSG免疫缺陷小鼠移植瘤模型；2.首次采用ALDEFLUOR商用试剂盒分离ALDH1+细胞，进一步鉴定出ALDH1+细胞可以高效富集人肾癌移植瘤干细胞；3.本研究组发现肾癌组织 ALDH1A1 的表达与肿瘤大小、 临床分期、淋巴结转移、血管侵袭及复发正相关；同时ALDH1A1的表达与患者的无病生存期和总生存期负相关。4. 本课题组发现ALDH1+细胞较ALDH1－细胞具有更强的抑制CD3+T细胞增殖和诱导CD3+T细胞凋亡的能力；ALDH1+细胞较ALDH1－细胞可以诱导生成更多的MDSC细胞；肿瘤组织浸润的Tc17比例与ALDH1阳性肾癌细胞比例正相关，肾癌患者肿瘤浸润的Tc17比例与MDSC比例正相关，提示Tc17细胞可能通过促进ALDH1阳性人肾癌干细胞募集MDSC诱导免疫逃逸，为肿瘤免疫逃逸机制提供新的理论基础和肿瘤免疫治疗提供新的手段和靶点。