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KRAS G12V neoantigen specific T cell receptor for adoptive T cell therapy against tumors
Dan Lu1,2,3, Yuan Chen1,2,4, Min Jiang1,2
1CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
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.
Insights
Researchers identified T cell receptors (TCRs) that target KRAS-G12V mutant neoantigens. These TCR-T cells demonstrated anti-tumor activity, highlighting their potential in cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- KRAS mutations are key drivers in various cancers and represent important therapeutic targets.
- T cell receptors (TCRs) can recognize tumor-specific neoantigens presented by human lymphocyte antigen (HLA) molecules, enabling targeted cancer immunotherapy.
Purpose of the Study:
- To identify and characterize TCRs specific for KRAS-G12V mutant neoantigens presented by HLA-A*11:01.
- To evaluate the anti-tumor efficacy of engineered TCR-T cells targeting KRAS-G12V in preclinical models.
Main Methods:
- Identification of TCRs specific for the KRAS-G12V 9-mer neoantigen in the context of HLA-A*11:01.
- Construction and in vitro characterization of TCR-T cells, assessing cytokine secretion and cytotoxicity against KRAS-G12V-expressing tumor cells.
- Evaluation of anti-tumor activity of TCR-T cells in preclinical mouse models.
Main Results:
- Two TCRs specific for the KRAS-G12V 9-mer neoantigen presented by HLA-A*11:01 were identified.
- Engineered TCR-T cells exhibited specific cytokine secretion and cytotoxicity against KRAS-G12V-mutant tumor cells.
- Preclinical studies demonstrated anti-tumor activity of the TCR-T cells in mouse models.
- Structural analysis revealed distinct conformations of the KRAS-G12V mutant peptide compared to wildtype and longer peptides, crucial for TCR recognition.
Conclusions:
- The study identified novel TCRs with therapeutic potential for KRAS-G12V-mutant cancers.
- Understanding the TCR-peptide-HLA interaction mechanisms provides insights for developing effective TCR-based immunotherapies.
- These TCRs demonstrate significant anti-tumor efficacy, supporting their advancement for clinical application in KRAS-mutant tumor treatment.
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