Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
Front Immunol. 2022 May 26;13:902709. doi: 10.3389/fimmu.2022.902709. eCollection 2022.
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-A02:01 and HLA-A03:01 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-A02:01 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-A02:01-positive human cancer cell line harboring the G12V mutation. Our data provide strong evidence that mutant RAS can be targeted by immunotherapy.
RAS 突变发生在大约 20%的所有癌症中，鉴于其克隆性、作为驱动突变的关键作用、与不良预后和不可用药性的关联，它们代表了免疫治疗的有吸引力的靶点。我们已经鉴定出源自密码子 12 突变 RAS（G12A、G12C、G12D、G12R、G12S 和 G12V）的免疫原性肽，这些肽与 HLA-A02:01 和 HLA-A03:01 结合，并引发强烈的肽特异性 CD8+T 细胞反应，表明存在针对这些突变 RAS 衍生肽的有效 CD8+T 细胞库，可以被动员。这些肽的锚定残基的改变增强了它们与 HLA-A02:01 分子的结合亲和力，并允许生成对用锚定修饰和原始肽脉冲的靶细胞有反应的 CD8+T 细胞。针对这些肽产生的细胞毒性 T 细胞特异性裂解表达突变 RAS 的肿瘤细胞。用包含锚定修饰的 9 -mer G12V 表位的长肽对转基因人源化 HLA-A2/DR1 小鼠进行疫苗接种，可产生对原始 9 -mer 以及对携带 G12V 突变的 HLA-A02:01 阳性人癌细胞系有反应的 CD8+T 细胞。我们的数据提供了强有力的证据，表明突变 RAS 可以通过免疫疗法靶向。
