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

Author

Listed:
  • Dan Lu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Capital Medical University, National Centre for Children’s Health)

  • Yuan Chen

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Guangxi Medical University)

  • Min Jiang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jie Wang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yiting Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Keke Ma

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Shenzhen Children’s Hospital)

  • 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
    University of Chinese Academy of Sciences
    Shenzhen Children’s Hospital
    Beijing Life Science Academy)

  • George F. Gao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Beijing Life Science Academy)

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.

Suggested Citation

  • 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 & George F, 2023. "KRAS G12V neoantigen specific T cell receptor for adoptive T cell therapy against tumors," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42010-1
    DOI: 10.1038/s41467-023-42010-1
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    References listed on IDEAS

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    1. Andrew Poole & Vijaykumar Karuppiah & Annabelle Hartt & Jaafar N. Haidar & Sylvie Moureau & Tomasz Dobrzycki & Conor Hayes & Christopher Rowley & Jorge Dias & Stephen Harper & Keir Barnbrook & Miriam , 2022. "Therapeutic high affinity T cell receptor targeting a KRASG12D cancer neoantigen," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Yulei Zhao & Yonina R. Murciano-Goroff & Jenny Y. Xue & Agnes Ang & Jessica Lucas & Trang T. Mai & Arnaud F. Cruz Paula & Anne Y. Saiki & Deanna Mohn & Pragathi Achanta & Ann E. Sisk & Kanika S. Arora, 2021. "Diverse alterations associated with resistance to KRAS(G12C) inhibition," Nature, Nature, vol. 599(7886), pages 679-683, November.
    3. Adham S. Bear & Tatiana Blanchard & Joseph Cesare & Michael J. Ford & Lee P. Richman & Chong Xu & Miren L. Baroja & Sarah McCuaig & Christina Costeas & Khatuna Gabunia & John Scholler & Avery D. Posey, 2021. "Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
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    Cited by:

    1. Andrew C. McShan & David Flores-Solis & Yi Sun & Samuel E. Garfinkle & Jugmohit S. Toor & Michael C. Young & Nikolaos G. Sgourakis, 2023. "Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. John P. Finnigan & Jenna H. Newman & Yury Patskovsky & Larysa Patskovska & Andrew S. Ishizuka & Geoffrey M. Lynn & Robert A. Seder & Michelle Krogsgaard & Nina Bhardwaj, 2024. "Structural basis for self-discrimination by neoantigen-specific TCRs," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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