T cell receptors employ diverse strategies to target a p53 cancer neoantigen.
T cell receptors employ diverse strategies to target a p53 cancer neoantigen.
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DOI：
10.1016/j.jbc.2022.101684
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Mariuzza RA
中科院分区：
文献类型：
--
作者：
Wu D;Gowathaman R;Pierce BG;Mariuzza RA
肿瘤特异性T细胞的过继细胞治疗可以调节持久的癌症消退。肿瘤特异性T细胞的主要靶点是恶性转化过程中自身蛋白突变所产生的新抗原。为了在原子水平上了解T细胞对肿瘤新抗原的识别，我们研究了寡克隆T细胞受体(TCR)，它识别由主要组织相容性复合体I类分子HLA-A2呈现的p53癌基因(P53R175H)的驱动突变产生的新表位。我们先前报道了三个p53R175H特异的TCR(38-10，12-6和1a2)与p53R175H和HLA-A2结合的结构。这些结构表明，这些TCR通过与R175H突变形成广泛的相互作用来区分WT和突变的P53。在这里，我们报告了第四个p53R175H特异性TCR(6-11)的结构，该TCR与p53R175H和HLA-A2形成复合体。与38-10、12-6和1a2相比，TCR6-11与R175H突变没有直接接触，但仍然能够区分突变型和WTP53。基于结构的电子诱变表明，与p53R175H相比，WT p53与6-11的结合亲和力损失了60倍，这主要是由于在复合体形成过程中，WT p53多肽中的R175比突变体中的H175具有更高的能量成本。这种通过6-11优先识别新抗原的间接策略从根本上不同于其他TCR采用的直接策略，并突显了识别p53R175H的解决方案的多样性，具有足够的选择性来介导T细胞对肿瘤而不是正常细胞的杀伤。
Adoptive cell therapy with tumor-specific T cells can mediate durable cancer regression. The prime target of tumor-specific T cells are neoantigens arising from mutations in self-proteins during malignant transformation. To understand T cell recognition of cancer neoantigens at the atomic level, we studied oligoclonal T cell receptors (TCRs) that recognize a neoepitope arising from a driver mutation in the p53 oncogene (p53R175H) presented by the major histocompatibility complex class I molecule HLA-A2. We previously reported the structures of three p53R175H-specific TCRs (38-10, 12-6, and 1a2) bound to p53R175H and HLA-A2. The structures showed that these TCRs discriminate between WT and mutant p53 by forming extensive interactions with the R175H mutation. Here, we report the structure of a fourth p53R175H-specific TCR (6-11) in complex with p53R175H and HLA-A2. In contrast to 38-10, 12-6, and 1a2, TCR 6-11 makes no direct contacts with the R175H mutation, yet is still able to distinguish mutant from WT p53. Structure-based in silico mutagenesis revealed that the 60-fold loss in 6-11 binding affinity for WT p53 compared to p53R175H is mainly due to the higher energetic cost of desolvating R175 in the WT p53 peptide during complex formation than H175 in the mutant. This indirect strategy for preferential neoantigen recognition by 6-11 is fundamentally different from the direct strategies employed by other TCRs and highlights the multiplicity of solutions to recognizing p53R175H with sufficient selectivity to mediate T cell killing of tumor but not normal cells.
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DOI：
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发表时间：
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期刊：
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影响因子：
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DOI：
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发表时间：
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期刊：
Science (New York, N.Y.)
影响因子：
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