Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy.
Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy.
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DOI：
10.3389/fimmu.2017.01210
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发表时间：
2017
影响因子：
7.3
通讯作者：
Vieira GF
中科院分区：
文献类型：
--
作者：
Antunes DA;Rigo MM;Freitas MV;Mendes MFA;Sinigaglia M;Lizée G;Kavraki LE;Selin LK;Cornberg M;Vieira GF
免疫疗法已成为最有前途的癌症治疗途径之一，利用患者自身的免疫系统来消除癌细胞。基于 T 细胞的免疫疗法的临床试验显示肿瘤显着消退，对多种癌症类型和许多不同的患者有效。不幸的是，这一进展因严重（甚至致命）副作用的报道而受到影响。此类疗法依赖于细胞毒性 T 细胞淋巴细胞的使用，细胞毒性 T 细胞淋巴细胞是适应性免疫系统的重要组成部分。细胞毒性 T 细胞经常参与监视，能够消除患病细胞并产生保护性免疫记忆。给定 T 细胞的特异性是通过 T 细胞受体 (TCR) 和负载肽的主要组织相容性复合物 (MHC) 之间的结构相互作用来确定的；即，由 MHC 分子在细胞表面展示的细胞内肽配体。然而，给定的 TCR 可以识别不同的肽-MHC (pMHC) 复合物，这有时会引发不需要的反应，即 T 细胞交叉反应性。在黑色素瘤特异性 T 细胞对健康组织（例如心脏和神经系统）造成细胞毒性损伤的报道之后，这已成为基于 TCR 的免疫疗法的一个主要安全问题。 T 细胞交叉反应性已在病毒免疫学和组织移植领域得到广泛研究。越来越多的证据表明，这在很大程度上是由看似不相关的 pMHC 复合体的结构相似性驱动的。在这里，我们回顾了最近关于 pMHC 交叉反应性“热点”存在的报道，并提出了 TCR 相互作用谱的存在（即，对更一般的 TCR 足迹的改进，其中一些氨基酸残基在触发 T 细胞交叉反应性方面比其他氨基酸残基更重要）。我们还利用现有的结构数据和 pMHC 模型来解释先前报道的病毒衍生肽之间的交叉反应模式。我们的研究提供了进一步的证据，表明 pMHC 复合物的结构分析可用于评估肽靶点之间交叉反应的内在可能性。此外，我们假设所报道的交叉反应中的一些明显的不一致，例如优先方向性，也可能是由目标 pMHC 复合物的特定结构特征驱动的。最后，我们解释了为什么基于 TCR 的免疫疗法提供了可以做出有意义的 T 细胞交叉反应预测的特殊背景。
Immunotherapy has become one of the most promising avenues for cancer treatment, making use of the patient’s own immune system to eliminate cancer cells. Clinical trials with T-cell-based immunotherapies have shown dramatic tumor regressions, being effective in multiple cancer types and for many different patients. Unfortunately, this progress was tempered by reports of serious (even fatal) side effects. Such therapies rely on the use of cytotoxic T-cell lymphocytes, an essential part of the adaptive immune system. Cytotoxic T-cells are regularly involved in surveillance and are capable of both eliminating diseased cells and generating protective immunological memory. The specificity of a given T-cell is determined through the structural interaction between the T-cell receptor (TCR) and a peptide-loaded major histocompatibility complex (MHC); i.e., an intracellular peptide–ligand displayed at the cell surface by an MHC molecule. However, a given TCR can recognize different peptide–MHC (pMHC) complexes, which can sometimes trigger an unwanted response that is referred to as T-cell cross-reactivity. This has become a major safety issue in TCR-based immunotherapies, following reports of melanoma-specific T-cells causing cytotoxic damage to healthy tissues (e.g., heart and nervous system). T-cell cross-reactivity has been extensively studied in the context of viral immunology and tissue transplantation. Growing evidence suggests that it is largely driven by structural similarities of seemingly unrelated pMHC complexes. Here, we review recent reports about the existence of pMHC “hot-spots” for cross-reactivity and propose the existence of a TCR interaction profile (i.e., a refinement of a more general TCR footprint in which some amino acid residues are more important than others in triggering T-cell cross-reactivity). We also make use of available structural data and pMHC models to interpret previously reported cross-reactivity patterns among virus-derived peptides. Our study provides further evidence that structural analyses of pMHC complexes can be used to assess the intrinsic likelihood of cross-reactivity among peptide-targets. Furthermore, we hypothesize that some apparent inconsistencies in reported cross-reactivities, such as a preferential directionality, might also be driven by particular structural features of the targeted pMHC complex. Finally, we explain why TCR-based immunotherapy provides a special context in which meaningful T-cell cross-reactivity predictions can be made.
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影响因子：
3.2
作者：
D'Orsogna, L. J.;Roelen, D. L.;Doxiadis, I. I. N.;Claas, F. H. J.
通讯作者：
Claas, F. H. J.
影响因子：
32.4
作者：
Adams JJ;Narayanan S;Liu B;Birnbaum ME;Kruse AC;Bowerman NA;Chen W;Levin AM;Connolly JM;Zhu C;Kranz DM;Garcia KC
通讯作者：
Garcia KC
影响因子：
64.5
作者：
Birnbaum ME;Mendoza JL;Sethi DK;Dong S;Glanville J;Dobbins J;Ozkan E;Davis MM;Wucherpfennig KW;Garcia KC
通讯作者：
Garcia KC
影响因子：
14.9
作者：
Clark K;Karsch-Mizrachi I;Lipman DJ;Ostell J;Sayers EW
通讯作者：
Sayers EW
影响因子：
5.5
作者：
Fytili, P.;Dalekos, G. N.;Wedemeyer, H.
通讯作者：
Wedemeyer, H.