Rational discovery of a cancer neoepitope harboring the KRAS G12D driver mutation  

作　　者：Peng Bai Qiuping Zhou Pengcheng Wei Hua Bai Sanny K.Chan John W.Kappler Philippa Marrack Lei Yin 

机构地区：[1]State Key Laboratory of Virology,Hubei Key Laboratory of Cell Homeostasis,College of Life Sciences,Wuhan University,Wuhan 430072,China [2]Department of Biomedical Research,National Jewish Health,Denver CO 80206,USA [3]Department of Pediatrics,University of Colorado Denver School of Medicine,Aurora CO 80045,USA [4]Division of Pediatric Allergy-Immunology,National Jewish Health,Denver CO 80206,USA [5]Barbara Davis Center for Childhood Diabetes,University of Colorado,Aurora CO 80045,USA [6]Department of Immunology and Microbiology,University of Colorado School of Medicine,Aurora CO 80045,USA [7]Structural Biology and Biochemistry program,University of Colorado Anschutz Medical Campus,Aurora CO 80045,USA [8]Department of Biochemistry and Molecular Genetics,University of Colorado Anschutz Medical Campus,Aurora CO 80045,USA

出　　处：《Science China(Life Sciences)》2021年第12期2144-2152,共9页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China(31870728,31470738,and 32000611);the National Basic Research Program of China(2014CB910103);the Fundamental Research Funds for the Central Universities(2042020kfxg02);the China Postdoctoral Science Foundation(2018M642918)。

摘　　要：Cytotoxic T cells targeting cancer neoantigens harboring driver mutations can lead to durable tumor regression in an HLAIdependent 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-ofconcept 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.

关 键 词：cancer immunology major histocompatibility complex(MHC) vaccine neoantigen prediction antigen immunogenicity 

分 类 号：R730.51[医药卫生—肿瘤]