State Key Laboratory of Virology, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
Department of Biomedical Research, National Jewish Health, Denver, CO, 80206, USA.
Sci China Life Sci. 2021 Dec;64(12):2144-2152. doi: 10.1007/s11427-020-1888-1. Epub 2021 Mar 16.
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.
靶向携带驱动突变的癌症新生抗原的细胞毒性 T 细胞可以以 HLAI 依赖的方式导致持久的肿瘤消退。然而，要扩大有资格接受基于新抗原的免疫治疗的患者群体是很困难的，因为免疫原性新抗原-HLA 对在不同患者之间很少共享。因此，需要找到其他人类白细胞抗原（HLA）等位基因，这些等位基因也可以呈现出临床有效的新抗原。最近，针对 HLA-C*08:02 患者 KRAS G12D 突变的基于新抗原的免疫疗法已显示出有效性。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的组合）来寻找可能也能呈现 KRAS G12D 新抗原的潜在 HLA 等位基因。与基于计算的结合预测相比，该策略避免了不同 HLA 等位基因之间的准确性不均匀。我们的发现扩大了有资格接受针对 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-HLA 对的替代方法，最大限度地提高了共享新抗原的临床应用。
