Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocyte's and mediates lysis of tumor cells
Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocyte's and mediates lysis of tumor cells
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DOI：
10.1073/pnas.182418399
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发表时间：
2002-09-17
影响因子：
11.1
通讯作者：
Zanetti, M
中科院分区：
文献类型：
--
作者：
Hernández, J;García-Pons, F;Zanetti, M
端粒酶逆转录酶（TRT）是一种在绝大多数人类肿瘤中表达的肿瘤相关抗原，目前是治疗性癌症疫苗最有希望的靶标候选之一。TRT在某些特定组织中也有低水平表达，应被视为一种自身抗原。在本研究中，我们试图诱导针对人（h）TRT肽的细胞毒性T淋巴细胞（CTL）反应，这些肽具有较低的相对亲和力，其可用的T细胞库可能优先避开耐受。这是通过使用hTRT的类似物肽来实现的，其对主要组织相容性复合体（MHC）的相对亲和力通过在第一位进行靶向（→酪氨酸）替换而增加。通过用这些类似物肽免疫HLA - A2.1转基因小鼠，我们鉴定出一种这样的低相对亲和力肽（p572），它在肿瘤细胞中由HLA - A2.1内源性加工和呈递，并被特异性CTL识别。我们使用这种高免疫原性的类似物肽在癌症患者和正常供体中成功诱导出TRT特异性CTL。针对p572的CTL能够裂解人类和小鼠肿瘤细胞，但不裂解活化的自体B细胞。因此，这种肽是基于TRT底物的癌症疫苗的一个重要候选成分，并验证了针对MHC低亲和力肽用于癌症免疫治疗的策略。
Telomerase reverse transcriptase (TRT) is a tumor-associated antigen expressed in the vast majority of human tumors and is presently one of the most promising target candidates for a therapeutic cancer vaccine. TRT is also expressed at low level in selected tissues and should be considered a self antigen. In the present study we sought to develop cytotoxic T lymphocytes (CTL) responses directed against human (h)TRT peptides with low relative affinity for which the available repertoire is to be preferentially spared from tolerance. This was accomplished by using analogue peptides of hTRT whose relative affinity for the MHC was increased by a targeted (-->Tyr) substitution in position one. By immunizing HLA A2.1 transgenic mice with these analogue peptides, we identified one such low relative affinity peptide (p572) that is endogenously processed and presented by HLA A2.1 in tumor cells, and is recognized by specific CTL. We used the highly immunogenic analogue peptide to successfully induce TRT-specific CTL in cancer patients and normal donors. CTL against p572-lysed human and mouse tumor cells but not activated autologous B cells. This peptide represents, therefore, an important candidate component of a cancer vaccine based on a TRT substrate and validates the strategy of targeting peptides with low affinity for the MHC for cancer immunotherapy.