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Cited by 101Immunotherapy and Immune ResponsesCAR-T cell therapy researchCancer Immunotherapy and Biomarkers

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

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Lu, Dan, Chen, Yuan, Jiang, Min, Wang, Jie, Li, Yiting, Ma, Keke, Sun, Wenqiao, Zheng, Xing +8 more·2023·Nature Communications
DOI 10.1038/s41467-023-42010-1PMC PMC10570350
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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.

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  • Additional emerging modalities for KRAS-targeted therapy include RNA-targeted therapeutics, antisense oligonucleotides, siRNA-based suppression, neoantigen vaccines, and adoptive T-cell therapies targeting mutant KRAS-derived epitopes.

    “Additional emerging modalities include RNA-targeted therapeutics, antisense oligonucleotides, siRNA-based suppression [65,66], neoantigen vaccines [67,68], and adoptive T-cell therapies targeting mutant KRAS-derived epitopes [69,70].”

    From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [70]

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Cited by

Sorted by citations

Authors
Lu, D., Chen, Y., Jiang, M., Wang, J., Li, Y., Ma, K., Sun, W., Zheng, X., Qi, J., Jin, W., Chen, Y., Chai, Y., Zhang, C. W. H., Liang, H., Tan, S., & Gao, G. F.
Affiliations
  • Capital Medical University (CN)
  • Guangxi Medical University (CN)
  • Chinese Academy of Sciences (CN)
Corresponding author
  • Tan, Shuguang
  • Gao, George F.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-10-12
Volume
14
Issue
1
Pages
6389-6389
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-42010-1
PMC
PMC10570350
OpenAlex
W4387576459
Cited by
101
References
6
Citations by year
2026: 34 · 2025: 43 · 2024: 22 · 2023: 2
FWCI
11.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (32222031, 2022YFC2302900, 92169208, YSBR-083)
  • Chinese Academy of Sciences (YSBR-083)
  • National Key Research and Development Program of China (2022YFC2302900, 2021YFC2301400)
  • Institute of Genetics
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
KRAS G12V mutation, neoantigens, T cell receptor, adoptive T cell therapy, HLA-A*11:01, peptide conformation, cancer immunotherapy, anticancer activity, T cell cytotoxicity
MeSH terms
Animals, Antigens, Neoplasm, Female, Humans, Neoplasms, Peptides, Receptors, Antigen, T-Cell, Proto-Oncogene Proteins p21(ras), Mice, Cell- and Tissue-Based Therapy

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