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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >CD8~+ T cell responses against a dominant cryptic HLA-A2 epitope after NY-ESO-1 peptide immunization of cancer patients
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CD8~+ T cell responses against a dominant cryptic HLA-A2 epitope after NY-ESO-1 peptide immunization of cancer patients

机译：NY-ESO-1肽免疫癌症患者后，CD8〜+ T细胞对显性隐性HLA-A2表位的反应

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摘要

NY-ESO-1 is a germ cell antigen aberrantly expressed in different tumor types that elicits strong humoral and cellular immune responses in cancer patients. Monitoring spontaneous CD8~+ T cell responses against NY-ESO-1 peptides 157-165 (S9C) and 157-167 (S11L) in a series of HLA-A2~+ cancer patients showed that these two peptides had overlapping antigenic profiles and were equally immunogenic. However, discrepancies between S9C and S11L reactivities were observed upon vaccination with both peptides to generate or boost T cell responses to NY-ESO-1 in cancer patients. We here analyze the fine specificity of these responses and describe an HLA-A2-restricted epitope, NY-ESO-1 peptide 159-167 (L9L), which is strongly recognized by CD8~+ T cells as a result of peptide vaccination of cancer patients. Responses to L9L were stimulated by S11L and appeared early in the course of vaccination, independently of S9C responses. However, L9L-specif ic CD8~+ T cells failed to recognize tumor cells naturally expressing NY-ESO-1 or B lymphoblastoid cells transduced with NY-ESO-1. Processing of L9L could be rescued after IFN-γ treatment of tumor cells or by dendritic cells pulsed with NY-ESO-1 protein/antibody immune complexes. The present results demonstrate a dual specificity within peptide S11L, with S9C as the natural antigenic tumor epitope, and L9L as a cryptic epitope with dominant immunoge-nicity upon vaccination that diverts the immune response from tumor recognition. These unanticipated findings raise questions about the use of S11L in the clinic and emphasize the importance of analyzing the fine specificity of vaccine-induced T cell responses in patients as a basis for constructing effective cancer vaccines.
机译：NY-ESO-1是一种在不同肿瘤类型中异常表达的生殖细胞抗原，在癌症患者中引起强烈的体液和细胞免疫应答。监测一系列HLA-A2〜+癌症患者对NY-ESO-1肽157-165（S9C）和157-167（S11L）的自发性CD8 + T细胞反应，发现这两种肽具有重叠的抗原谱，并且同样具有免疫原性。然而，在用两种肽接种以在癌症患者中产生或增强对NY-ESO-1的T细胞应答后，观察到S9C和S11L反应性之间的差异。我们在这里分析这些反应的精细特异性，并描述一种HLA-A2限制性表位，NY-ESO-1肽159-167（L9L），由于癌症的肽疫苗接种，CD8〜+ T细胞强烈识别该抗原表位耐心。 S11L刺激了对L9L的反应，并在疫苗接种过程的早期出现，与S9C反应无关。然而，L9L特异性CD8 + T细胞不能识别天然表达NY-ESO-1或由NY-ESO-1转导的B淋巴母细胞的肿瘤细胞。 IFN-γ处理肿瘤细胞后，或通过用NY-ESO-1蛋白/抗体免疫复合物脉冲刺激的树突状细胞，可以挽救L9L的加工。本结果证明了肽S11L内的双重特异性，其中S9C为天然抗原性肿瘤表位，而L9L为隐性表位，其在接种疫苗后具有显着的免疫原性，从而转移了从肿瘤识别的免疫应答。这些出乎意料的发现提出了有关在临床中使用S11L的疑问，并强调了分析患者中疫苗诱导的T细胞反应的精细特异性作为构建有效的癌症疫苗的基础的重要性。

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