KRAS G12V neoantigen specific T cell receptor for adoptive T cell therapy against tumors

Dan Lu, Yuan Chen, Min Jiang, Jie Wang, Yiting Li, Keke Ma, Wenqiao Sun, Xing Zheng, Jianxun Qi, Wenjing Jin, Yu Chen, Yan Chai, Catherine W. H. Zhang, Hao Liang, Shuguang Tan () and George F. Gao ()
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Dan Lu: Chinese Academy of Sciences
Yuan Chen: Chinese Academy of Sciences
Min Jiang: Chinese Academy of Sciences
Jie Wang: Chinese Academy of Sciences
Yiting Li: Chinese Academy of Sciences
Keke Ma: Chinese Academy of Sciences
Wenqiao Sun: Chinese Academy of Sciences
Xing Zheng: Chinese Academy of Sciences
Jianxun Qi: Chinese Academy of Sciences
Wenjing Jin: YKimmu (Beijing) Biotechnology Co., Ltd
Yu Chen: YKimmu (Beijing) Biotechnology Co., Ltd
Yan Chai: Chinese Academy of Sciences
Catherine W. H. Zhang: YKimmu (Beijing) Biotechnology Co., Ltd
Hao Liang: Guangxi Medical University
Shuguang Tan: Chinese Academy of Sciences
George F. Gao: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract KRAS mutations are broadly recognized as promising targets for tumor therapy. T cell receptors (TCRs) can specifically recognize KRAS mutant neoantigens presented by human lymphocyte antigen (HLA) and mediate T cell responses to eliminate tumor cells. In the present study, we identify two TCRs specific for the 9-mer KRAS-G12V mutant neoantigen in the context of HLA-A*11:01. The TCR-T cells are constructed and display cytokine secretion and cytotoxicity upon co-culturing with varied tumor cells expressing the KRAS-G12V mutation. Moreover, 1-2C TCR-T cells show anti-tumor activity in preclinical models in female mice. The 9-mer KRAS-G12V mutant peptide exhibits a distinct conformation from the 9-mer wildtype peptide and its 10-mer counterparts. Specific recognition of the G12V mutant by TCR depends both on distinct conformation from wildtype peptide and on direct interaction with residues from TCRs. Our study reveals the mechanisms of presentation and TCR recognition of KRAS-G12V mutant peptide and describes TCRs with therapeutic potency for tumor immunotherapy.

Date: 2023
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DOI: 10.1038/s41467-023-42010-1

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