CD8型
细胞毒性T细胞
表位
突变体
免疫疗法
癌症免疫疗法
生物
肽
癌症研究
突变
人类白细胞抗原
T细胞
分子生物学
抗原
免疫学
免疫系统
遗传学
生物化学
基因
体外
作者
Renato B. Baleeiro,Louisa S. Chard,Peng Liu,Shuangshuang Lu,Yu‐Chun Lone,Nicholas R. Lemoine,Yaohe Wang
标识
DOI:10.3389/fimmu.2022.902709
摘要
RAS mutations occur in approximately 20% of all cancers and given their clonality, key role as driver mutation, association with poor prognosis and undruggability, they represent attractive targets for immunotherapy. We have identified immunogenic peptides derived from codon 12 mutant RAS (G12A, G12C, G12D, G12R, G12S and G12V), which bind to HLA-A*02:01 and HLA-A*03:01 and elicit strong peptide-specific CD8+ T cell responses, indicating that there is an effective CD8+ T-cell repertoire against these mutant RAS-derived peptides that can be mobilized. Alterations in anchor residues of these peptides enhanced their binding affinity to HLA-A*02:01 molecules and allowed generation of CD8+ T cells that responded to target cells pulsed with the anchor-modified and also with the original peptide. Cytotoxic T cells generated against these peptides specifically lysed tumor cells expressing mutant RAS. Vaccination of transgenic humanized HLA-A2/DR1 mice with a long peptide encompassing an anchor-modified 9-mer G12V epitope generated CD8+ T cells reactive to the original 9-mer and to a HLA-A*02:01-positive human cancer cell line harboring the G12V mutation. Our data provide strong evidence that mutant RAS can be targeted by immunotherapy.
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