Rational discovery of a cancer neoepitope harboring the KRAS G12D driver mutation
Rational discovery of a cancer neoepitope harboring the KRAS G12D driver mutation
复制标题
合理发现含有 KRAS G12D 驱动突变的癌症新表位
DOI：
10.1007/s11427-020-1888-1
复制
发表时间：
2021-03-16
影响因子：
9.1
通讯作者：
Yin, Lei
中科院分区：
文献类型：
--
作者：
Bai, Peng;Zhou, Qiuping;Yin, Lei
针对携带驱动突变的癌症新抗原的细胞毒性T细胞可以以HLAI依赖的方式导致持久的肿瘤消退。然而，很难扩大有资格接受基于新抗原的免疫治疗的患者群体，因为免疫原性新抗原-人类白细胞抗原对很少在不同的患者中共享。因此，需要一种方法来寻找其他人类白细胞抗原(HL A)等位基因，同时也能呈现临床上有效的新抗原。最近，针对KRAS G12D突变的新抗原免疫治疗在患有HLA-C*08：02的患者中显示出有效性。在一项概念验证研究中，我们提出了一种组合策略(系统发育和结构分析相结合)，以寻找也可以呈现KRAS G12D新抗原的潜在的HLA等位基因。与电子结合预测相比，该策略避免了不同等位基因之间准确性的不均衡。我们的发现扩大了有可能有资格接受针对KRAS G12D突变的免疫治疗的患者群体。此外，我们提供了一种预测新抗原-人类白细胞抗原对的替代方法，从而最大限度地提高了共享新抗原的临床应用。
Cytotoxic T cells targeting cancer neoantigens harboring driver mutations can lead to durable tumor regression in an HLAI-dependent manner. However, it is difficult to extend the population of patients who are eligible for neoantigen-based immunotherapy, as immunogenic neoantigen-HLA pairs are rarely shared across different patients. Thus, a way to find other human leukocyte antigen (HLA) alleles that can also present a clinically effective neoantigen is needed. Recently, neoantigen-based immunotherapy targeting the KRAS G12D mutation in patients with HLA-C*08:02 has shown effectiveness. In a proof-of-concept study, we proposed a combinatorial strategy (the combination of phylogenetic and structural analyses) to find potential HLA alleles that could also present KRAS G12D neoantigen. Compared to in silico binding prediction, this strategy avoids the uneven accuracy across different HLA alleles. Our findings extend the population of patients who are potentially eligible for immunotherapy targeting the KRAS G12D mutation. Additionally, we provide an alternative way to predict neoantigen-HLA pairs, which maximizes the clinical usage of shared neoantigens.