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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells
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Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells

机译：与HLA A2.1低亲和力的人端粒酶逆转录酶肽的鉴定，该肽诱导细胞毒性T淋巴细胞并介导肿瘤细胞的裂解

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摘要

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.
机译：端粒酶逆转录酶（TRT）是一种在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在选定的组织中也低水平表达，应被视为自身抗原。在本研究中，我们寻求开发针对人亲和（h）TRT肽的细胞毒性T淋巴细胞（CTL）反应，该肽具有较低的相对亲和力，要优先利用这些相对分子库来避免耐受。这是通过使用hTRT的类似肽完成的，其对MHC的相对亲和力通过位置1的靶向（→Tyr）取代而增加。通过用这些类似物肽免疫HLA A2.1转基因小鼠，我们鉴定了一种这样的低相对亲和力肽（p572），它是由HLA A2.1在肿瘤细胞中内源加工并呈递的，并被特异性CTL识别。我们使用了高度免疫原性的类似物肽在癌症患者和正常供体中成功诱导了TRT特异性CTL。针对p572裂解的人和小鼠肿瘤细胞的CTL，但不激活自体B细胞。因此，该肽代表了基于TRT底物的癌症疫苗的重要候选成分，并验证了以低亲和力靶向MHC的肽靶向癌症免疫疗法的策略。

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