IN-VITRO INDUCTION OF HUMAN CYTOTOXIC T-LYMPHOCYTE RESPONSES AGAINST PEPTIDES OF MUTANT AND WILD-TYPE P53
IN-VITRO INDUCTION OF HUMAN CYTOTOXIC T-LYMPHOCYTE RESPONSES AGAINST PEPTIDES OF MUTANT AND WILD-TYPE P53
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DOI：
10.1002/eji.1830230905
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发表时间：
1993-09-01
影响因子：
5.4
通讯作者：
MELIEF, CJM
中科院分区：
文献类型：
--
作者：
HOUBIERS, JGA;NIJMAN, HW;MELIEF, CJM
p53抑癌基因产物在肿瘤发生中的中心作用正逐渐被阐明。p53肿瘤抑制基因中的点突变在大多数人类癌症中是常见的，并且通常与p53蛋白过表达相关。因此，过度表达的野生型或突变型p53蛋白决定簇代表了针对参与恶性转化的结构的癌症免疫治疗的有吸引力的靶点。实现这一目标的一个重要步骤是鉴定可以被人细胞毒性T淋巴细胞识别的p53表位。我们在体外试验中鉴定了能够与HLA-A2.1结合的（突变型）p53肽。这些HLA-A2.1结合肽用于使用人加工缺陷细胞系（174CEM.T2）作为抗原呈递细胞体外诱导初级细胞毒性T淋巴细胞应答。这些细胞展示“空”的HLA I类表面分子，可以有效地装载单个肽。我们获得了能够特异性裂解负载野生型或肿瘤特异性突变型p53肽的靶细胞的CD 8+细胞毒性T淋巴细胞克隆。该策略允许在体外启动针对所选靶分子的人细胞毒性T淋巴细胞应答。
The central role of the p53 tumor suppressor gene product in oncogenesis is gradually being clarified. Point mutations in the p53 tumor suppressor gene are common in most human cancers and are often associated with p53 protein overexpression. Overexpressed wild-type or mutant determinants of the p53 protein thus represent an attractive target for immunotherapy of cancer directed against a structure involved in malignant transformation. An important step towards this goal is identification of epitopes of p53 that can be recognized by human cytotoxic T lymphocytes. We identified peptides of (mutant) p53 capable of binding to HLA-A2.1 in an in vitro assay. These HLA-A2.1-binding peptides were utilized for in vitro induction of primary cytotoxic T lymphocyte responses using a human processing-defective cell line (174CEM.T2) as antigen-presenting cell. These cells display ''empty'' HLA class I surface molecules, that can efficiently be loaded with a single peptide. We obtained CD8+ cytotoxic T lymphocyte clones capable of specifically lysing target cells loaded with wild-type or tumor-specific mutant p53 peptides. This strategy allows the in vitro initiation of human cytotoxic T lymphocyte responses against target molecules of choice.