Structural and energetic evidence for highly peptide-specific tumor antigen targeting via allo-MHC restriction

Amy A. Simpson; Fiyaz Mohammed; Mahboob Salim; Amy Tranter; Alan B. Rickinson; Hans J. Stauss; Paul A. H. Moss; Neil M. Steven; Benjamin E. Willcox

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Structural and energetic evidence for highly peptide-specific tumor antigen targeting via allo-MHC restriction

机译：通过异源MHC限制高度靶向肽特异性肿瘤抗原的结构和能量证据

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Immunotherapies targeting peptides presented by allogeneic MHC molecules offer the prospect of circumventing tolerance to key tumor-associated self-antigens. However, the degree of antigen specificity mediated by alloreactive T cells, and their ability to discriminate normal tissues from transformed cells presenting elevated antigen levels, is poorly understood. We examined allorecognition of an HLA-A2-restricted Hodgkin's lymphoma-as-sociated antigen and were able to isolate functionally antigen-specific allo-HLA-A2-restricted T cells from multiple donors. Binding and structural studies, focused on a prototypic allo-HLA-A2-restricted T-cell receptor (TCR) termed NB20 derived from an HLA-A3 homozygote, suggested highly peptide-specific allorecognition that was energetically focused on antigen, involving direct recognition of a distinct allopeptide presented within a conserved MHC recognition surface. Although NB20/HLA-A2 affinity was unremarkable, TCR/MHC complexes were very short-lived, consistent with suboptimal TCR triggering and tolerance to low antigen levels. These data provide strong molecular evidence that within the functionally heterogeneous alloreactive repertoire, there is the potential for highly antigen-specific "allo-MHC-restricted" recognition and suggest a kinetic mechanism whereby allo-MHC-restricted T cells may discriminate normal from transformed tissue, thereby outlining a suitable basis for broad-based therapeutic targeting of tolerizing tumor antigens.

机译：针对同种异体MHC分子呈递的针对肽的免疫疗法为绕开对关键的肿瘤相关自身抗原的耐受性提供了前景。然而，对同种异体反应性T细胞介导的抗原特异性程度及其将正常组织与抗原水平升高的转化细胞区别开的能力了解甚少。我们检查了HLA-A2限制的霍奇金淋巴瘤相关抗原的同种异体认知，并能够从多个供体中分离出功能性抗原特异性的allo-HLA-A2限制的T细胞。结合和结构研究集中在原型原型异源HLA-A2限制性T细胞受体（TCR）上，其衍生自HLA-A3纯合子，称为NB20，表明高度肽特异性的同种异体识别主要集中在抗原上，涉及直接识别抗原。在保守的MHC识别表面内呈现的独特全肽。尽管NB20 / HLA-A2亲和力不明显，但TCR / MHC复合物的寿命很短，与次佳的TCR触发和对低抗原水平的耐受性一致。这些数据提供了有力的分子证据，表明在功能异质的同种反应性库中，存在高度抗原特异性的“ allo-MHC-restricted”识别的潜力，并提出了一种动力学机制，通过此机制，allo-MHC-restricted T细胞可以区分正常的转化组织，从而概述了耐受肿瘤抗原的广泛治疗靶向的合适基础。

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《Proceedings of the National Academy of Sciences of the United States of America》 |2011年第52期|p.21176-21181|共6页
作者
Amy A. Simpson; Fiyaz Mohammed; Mahboob Salim; Amy Tranter; Alan B. Rickinson; Hans J. Stauss; Paul A. H. Moss; Neil M. Steven; Benjamin E. Willcox;
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作者单位

Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;

Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;

Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;

Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;

Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;

Division of Infection and Immunity, Department of Immunology, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom;

Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;

Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;

Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
中图分类
关键词
alloreactivity; cancer; tumor-associated antigen; immunotherapy;

机译：变态反应癌症;肿瘤相关抗原免疫疗法;

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专利

1. A tumor escape variant that has lost one major histocompatibility complex class I restriction element induces specific CD8+ T cells to an antigen that no longer serves as a target. [J] . S Seung, J L Urban, H Schreiber The Journal of Experomental Medicine . 1993,第3期

机译：丢失了一个主要的组织相容性复合体I类限制性元件的肿瘤逃逸变异体诱导了特异性CD8 + T细胞产生不再用作靶标的抗原。
2. Activated human γδ T cells induce peptide-specific CD8+ T-cell responses to tumor-associated self-antigens [J] . AltvaterB., PschererS., LandmeierS., Cancer immunology, immunotherapy : . 2012,第3期

机译：活化的人γδT细胞诱导对肿瘤相关自身抗原的肽特异性CD8 + T细胞应答
3. Activated human γδ T cells induce peptide-specific CD8+ T-cell responses to tumor-associated self-antigens [J] . Bianca Altvater, Sibylle Pscherer, Silke Landmeier, Cancer Immunology, Immunotherapy . 2012,第3期

机译：活化的人γδT细胞诱导对肿瘤相关自身抗原的肽特异性CD8 + T细胞应答
4. HPMA Copolymer-Bound Doxorubicin Targeted with Monoclonal Antibody to Tumor-Specific Antigen of BCL1 Leukemia Cells Can Completely Cure Tumor-Bearing Mice and Establish Long- Term Immunological Memory to the Original Tumor [C] . Controlled Release Society annual meeting . 2004

机译：靶向具有BCL1白血病细胞的肿瘤特异性抗原的单克隆抗体的HPMA共聚的多柔比蛋白可以完全固化携带肿瘤的小鼠并对原始肿瘤建立长期免疫记忆
5. Targeting a self/tumor antigen expressed in the prostate for adoptive T cell immunotherapy of prostate cancer. [D] . Chou, Cassie K. 2012

机译：靶向前列腺中表达的自身/肿瘤抗原，用于前列腺癌的过继T细胞免疫疗法。
6. Structural and energetic evidence for highly peptide-specific tumor antigen targeting via allo-MHC restriction [O] . Amy A. Simpson, Fiyaz Mohammed, Mahboob Salim, 2011

机译：通过异源MHC限制高度靶向肽特异性肿瘤抗原的结构和能量证据
7. Structural and energetic evidence for highly peptide-specific tumor antigen targeting via allo-MHC restriction [O] . Simpson, Amy A., Mohammed, Fiyaz, Salim, Mahboob, 2011

机译：通过异源MHC限制高度靶向肽特异性肿瘤抗原的结构和能量证据

Structural and energetic evidence for highly peptide-specific tumor antigen targeting via allo-MHC restriction

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