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Neoantigen-specific CD8 T cells with high structural avidity preferentially reside in and eliminate tumors

Author

Listed:
  • Julien Schmidt

    (Agora Cancer Research Center
    Lausanne University Hospital
    Lausanne University Hospital (CHUV))

  • Johanna Chiffelle

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Marta A. S. Perez

    (Agora Cancer Research Center
    Swiss Institute of Bioinformatics (SIB))

  • Morgane Magnin

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Sara Bobisse

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Marion Arnaud

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Raphael Genolet

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Julien Cesbron

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • David Barras

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Blanca Navarro Rodrigo

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Fabrizio Benedetti

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Alexandra Michel

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Lise Queiroz

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Petra Baumgaertner

    (Agora Cancer Research Center
    Lausanne University Hospital (CHUV))

  • Philippe Guillaume

    (Agora Cancer Research Center
    Lausanne University Hospital
    Lausanne University Hospital (CHUV))

  • Michael Hebeisen

    (Agora Cancer Research Center)

  • Olivier Michielin

    (Lausanne University Hospital)

  • Tu Nguyen-Ngoc

    (Agora Cancer Research Center)

  • Florian Huber

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Melita Irving

    (Agora Cancer Research Center)

  • Stéphanie Tissot-Renaud

    (Agora Cancer Research Center
    Lausanne University Hospital (CHUV))

  • Brian J. Stevenson

    (Agora Cancer Research Center
    Lausanne University Hospital
    Swiss Institute of Bioinformatics (SIB))

  • Sylvie Rusakiewicz

    (Agora Cancer Research Center
    Lausanne University Hospital (CHUV))

  • Denarda Dangaj Laniti

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Michal Bassani-Sternberg

    (Agora Cancer Research Center
    Lausanne University Hospital)

  • Nathalie Rufer

    (Agora Cancer Research Center)

  • David Gfeller

    (Agora Cancer Research Center
    Swiss Institute of Bioinformatics (SIB))

  • Lana E. Kandalaft

    (Agora Cancer Research Center
    Lausanne University Hospital
    Lausanne University Hospital (CHUV))

  • Daniel E. Speiser

    (Agora Cancer Research Center)

  • Vincent Zoete

    (Agora Cancer Research Center
    Swiss Institute of Bioinformatics (SIB))

  • George Coukos

    (Agora Cancer Research Center
    Lausanne University Hospital
    Lausanne University Hospital)

  • Alexandre Harari

    (Agora Cancer Research Center
    Lausanne University Hospital)

Abstract

The success of cancer immunotherapy depends in part on the strength of antigen recognition by T cells. Here, we characterize the T cell receptor (TCR) functional (antigen sensitivity) and structural (monomeric pMHC-TCR off-rates) avidities of 371 CD8 T cell clones specific for neoantigens, tumor-associated antigens (TAAs) or viral antigens isolated from tumors or blood of patients and healthy donors. T cells from tumors exhibit stronger functional and structural avidity than their blood counterparts. Relative to TAA, neoantigen-specific T cells are of higher structural avidity and, consistently, are preferentially detected in tumors. Effective tumor infiltration in mice models is associated with high structural avidity and CXCR3 expression. Based on TCR biophysicochemical properties, we derive and apply an in silico model predicting TCR structural avidity and validate the enrichment in high avidity T cells in patients’ tumors. These observations indicate a direct relationship between neoantigen recognition, T cell functionality and tumor infiltration. These results delineate a rational approach to identify potent T cells for personalized cancer immunotherapy.

Suggested Citation

  • Julien Schmidt & Johanna Chiffelle & Marta A. S. Perez & Morgane Magnin & Sara Bobisse & Marion Arnaud & Raphael Genolet & Julien Cesbron & David Barras & Blanca Navarro Rodrigo & Fabrizio Benedetti &, 2023. "Neoantigen-specific CD8 T cells with high structural avidity preferentially reside in and eliminate tumors," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38946-z
    DOI: 10.1038/s41467-023-38946-z
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    1. Martin Lauss & Marco Donia & Katja Harbst & Rikke Andersen & Shamik Mitra & Frida Rosengren & Maryem Salim & Johan Vallon-Christersson & Therese Törngren & Anders Kvist & Markus Ringnér & Inge Marie S, 2017. "Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    2. Vinod P. Balachandran & Marta Łuksza & Julia N. Zhao & Vladimir Makarov & John Alec Moral & Romain Remark & Brian Herbst & Gokce Askan & Umesh Bhanot & Yasin Senbabaoglu & Daniel K. Wells & Charles Ia, 2017. "Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer," Nature, Nature, vol. 551(7681), pages 512-516, November.
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    Cited by:

    1. 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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