Structural basis for T cell recognition of cancer neoantigens and implications for predicting neoepitope immunogenicity.
Structural basis for T cell recognition of cancer neoantigens and implications for predicting neoepitope immunogenicity.
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DOI：
10.3389/fimmu.2023.1303304
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
肿瘤特异性T细胞的过继细胞治疗（ACT）已被证明可以介导持久的癌症消退。肿瘤特异性T细胞也是其他疗法的基础，尤其是癌症疫苗。肿瘤特异性T细胞的主要靶标是恶性转化过程中由自身抗原突变产生的新抗原。新抗原的检测对T细胞来说是一个重大挑战，因为它们与自身抗原具有高度的结构相似性，并且需要避免自身免疫。新抗原必须与其野生型亲本有多大的不同才能诱导T细胞反应，这一点尚不清楚。在这里，我们回顾了最近关于T细胞受体（TCR）识别来自癌基因的共享癌症新抗原的结构和生物物理研究，包括p53R175H、KRASG12D、KRASG12V、HHATp8F和PIK3CAH1047L。这些研究表明，在某些情况下，致癌突变通过加强肽- mhc结合来改善抗原呈递。在其他情况下，通过与TCR的直接相互作用，或通过能量驱动或其他不需要TCR与突变直接接触的间接策略来检测突变。我们还回顾了旨在识别细胞表面肽mhc的抗体（tcr模拟抗体），作为tcr靶向癌症新抗原的替代方案。最后，我们回顾了这一领域的最新计算进展，包括预测新表位免疫原性的努力，以及这些努力如何通过肽- mhc结合的结构信息和tcr对肽- mhc的识别来推进。
Adoptive cell therapy (ACT) with tumor-specific T cells has been shown to mediate durable cancer regression. Tumor-specific T cells are also the basis of other therapies, notably cancer vaccines. The main target of tumor-specific T cells are neoantigens resulting from mutations in self-antigens over the course of malignant transformation. The detection of neoantigens presents a major challenge to T cells because of their high structural similarity to self-antigens, and the need to avoid autoimmunity. How different a neoantigen must be from its wild-type parent for it to induce a T cell response is poorly understood. Here we review recent structural and biophysical studies of T cell receptor (TCR) recognition of shared cancer neoantigens derived from oncogenes, including p53R175H, KRASG12D, KRASG12V, HHATp8F, and PIK3CAH1047L. These studies have revealed that, in some cases, the oncogenic mutation improves antigen presentation by strengthening peptide–MHC binding. In other cases, the mutation is detected by direct interactions with TCR, or by energetically driven or other indirect strategies not requiring direct TCR contacts with the mutation. We also review antibodies designed to recognize peptide–MHC on cell surfaces (TCR-mimic antibodies) as an alternative to TCRs for targeting cancer neoantigens. Finally, we review recent computational advances in this area, including efforts to predict neoepitope immunogenicity and how these efforts may be advanced by structural information on peptide–MHC binding and peptide–MHC recognition by TCRs.
影响因子：
8
作者：
Dao T;Mun SS;Molvi Z;Korontsvit T;Klatt MG;Khan AG;Nyakatura EK;Pohl MA;White TE;Balderes PJ;Lorenz IC;O'Reilly RJ;Scheinberg DA
通讯作者：
Scheinberg DA