Human dendritic cells transfected with renal tumor RNA stimulate polyclonal T-cell responses against antigens expressed by primary and metastatic tumors.
Human dendritic cells transfected with renal tumor RNA stimulate polyclonal T-cell responses against antigens expressed by primary and metastatic tumors.
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发表时间：
2001-04
期刊：
影响因子：
11.2
通讯作者：
Axel Heiser;Margaret A. Maurice;Donna R. Yancey;Doris Coleman;Philipp Dahm;J. Vieweg
中科院分区：
文献类型：
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作者：
Axel Heiser;Margaret A. Maurice;Donna R. Yancey;Doris Coleman;Philipp Dahm;J. Vieweg
尽管肾细胞癌已被证明对免疫治疗有反应，但肾细胞癌特异性排斥抗原及其相应的CTL表位很少被描述。使用从肿瘤细胞中分离的mRNA转染的树突状细胞（dc）可能允许特异性免疫治疗，甚至在尚未确定有效排斥抗原的癌症中。本研究表明，用从肾癌组织中分离的RNA转染的树突状细胞在体外刺激肿瘤特异性t细胞反应方面非常有效，但不与正常组织抗原（包括肾实质表达的抗原）交叉反应。相比之下，肿瘤特异性ctl可以裂解异体肿瘤，但不能裂解异体正常组织靶点，这表明肾癌中存在着尽管尚未识别的共同抗原。CTL对端粒酶逆转录酶（TERT）的反应在一定程度上解释了抗同种异体肿瘤的反应性，因为肾肿瘤rna转染的dc刺激了多克隆CTL反应，其中包括对TERT的反应。尽管如此，肿瘤特异性ctl在识别和裂解肿瘤靶点方面始终优于用TERT rna转染的dc刺激的ctl，这表明肿瘤特异性ctl代表一种多克隆反应，比针对TERT形式的单一抗原的t细胞反应提供更有效的抗肿瘤活性。肿瘤rna转染的dc不仅能够刺激t细胞对原发肿瘤的反应，也能够刺激t细胞对转移性肿瘤的反应，尽管这些组织表达的抗原库存在明显的离散差异。因此，总肿瘤rna转染的dc可能是一种广泛适用的疫苗策略，可在肾癌患者中诱导多克隆和潜在的治疗性t细胞反应。
Although renal cell carcinoma has been shown to respond to immunotherapy, renal cell carcinoma-specific rejection antigens and their corresponding CTL epitopes have rarely been described. The use of dendritic cells (DCs) transfected with mRNA isolated from tumor cells may allow specific immunotherapy even in cancers for which potent rejection antigens have not been identified. Here we show that DCs transfected with RNA isolated from renal cancer tissue are remarkably effective in stimulating tumor-specific T-cell response in vitro but do not cross-react with normal tissue antigens including antigens expressed by renal parenchyma. In contrast, the tumor-specific CTLs lysed allogeneic tumor but not allogeneic normal tissue targets, suggesting the presence of shared albeit unidentified antigens among renal carcinomas. CTL responses against telomerase reverse transcriptase (TERT) accounted in part for the reactivities against allogeneic tumors because renal tumor RNA-transfected DCs stimulated polyclonal CTL responses, which encompassed as a subcomponent a response against TERT. Nonetheless, the tumor-specific CTLs were consistently superior to the CTLs stimulated with TERT RNA-transfected DCs in recognizing and lysing tumor targets, suggesting that tumor-specific CTLs represent a polyclonal response providing more effective antitumor activity than T-cell responses directed against a single antigen in the form of TERT. Tumor RNA-transfected DCs were capable of stimulating T-cell reactivities not only against the primary tumor but also against metastatic tumors, although discrete differences in the antigenic repertoire expressed by these tissues were apparent. Thus, total tumor RNA-transfected DCs may represent a broadly applicable vaccine strategy to induce polyclonal and potentially therapeutic T-cell responses in renal cancer patients.