克拉斯
T细胞受体
癌症免疫疗法
生物
癌症研究
免疫疗法
病毒癌基因
突变
突变体
人类白细胞抗原
受体
体细胞
T细胞
癌基因
癌症
分子生物学
遗传学
抗原
计算生物学
结直肠癌
免疫系统
基因
细胞周期
作者
Mengyu Zhang,Wei Xu,Lingjie Luo,Fangxiao Guan,Xiangyao Wang,Pei Zhu,Jiexin Zhang,Xuyu Zhou,Feng Wang,Sheng Ye
标识
DOI:10.1038/s42003-024-06209-2
摘要
Abstract Neoantigens derived from somatic mutations in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), the most frequently mutated oncogene, represent promising targets for cancer immunotherapy. Recent research highlights the potential role of human leukocyte antigen (HLA) allele A*11:01 in presenting these altered KRAS variants to the immune system. In this study, we successfully generate and identify murine T-cell receptors (TCRs) that specifically recognize KRAS 8–16 G12V from three predicted high affinity peptides. By determining the structure of the tumor-specific 4TCR2 bound to KRAS G12V -HLA-A*11:01, we conduct structure-based design to create and evaluate TCR variants with markedly enhanced affinity, up to 15.8-fold. This high-affinity TCR mutant, which involved only two amino acid substitutions, display minimal conformational alterations while maintaining a high degree of specificity for the KRAS G12V peptide. Our research unveils the molecular mechanisms governing TCR recognition towards KRAS G12V neoantigen and yields a range of affinity-enhanced TCR mutants with significant potential for immunotherapy strategies targeting tumors harboring the KRAS G12V mutation.
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