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Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy

Author

Listed:
  • Marcel P. Trefny

    (University of Basel and University Hospital of Basel)

  • Nicole Kirchhammer

    (University of Basel and University Hospital of Basel)

  • Priska Auf der Maur

    (University of Basel and University Hospital of Basel)

  • Marina Natoli

    (University of Basel and University Hospital of Basel)

  • Dominic Schmid

    (University of Basel and University Hospital of Basel)

  • Markus Germann

    (University of Basel and University Hospital of Basel)

  • Laura Fernandez Rodriguez

    (University of Basel and University Hospital of Basel)

  • Petra Herzig

    (University of Basel and University Hospital of Basel)

  • Jonas Lötscher

    (University of Basel and University Hospital of Basel)

  • Maryam Akrami

    (University of Basel and University Hospital of Basel)

  • Jane C. Stinchcombe

    (Cambridge Institute for Medical Research, Biomedical Campus)

  • Michal A. Stanczak

    (University of Basel and University Hospital of Basel)

  • Andreas Zingg

    (University of Basel and University Hospital of Basel)

  • Melanie Buchi

    (University of Basel and University Hospital of Basel)

  • Julien Roux

    (University of Basel and University Hospital of Basel
    Swiss Institute of Bioinformatics)

  • Romina Marone

    (University of Basel and University Hospital of Basel
    Basel University Hospital)

  • Leyla Don

    (University of Basel and University Hospital of Basel)

  • Didier Lardinois

    (University Hospital Basel)

  • Mark Wiese

    (University Hospital Basel)

  • Lukas T. Jeker

    (University of Basel and University Hospital of Basel
    Basel University Hospital)

  • Mohamed Bentires-Alj

    (University of Basel and University Hospital of Basel)

  • Jérémie Rossy

    (University of Konstanz)

  • Daniela S. Thommen

    (University of Basel and University Hospital of Basel
    Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute)

  • Gillian M. Griffiths

    (Cambridge Institute for Medical Research, Biomedical Campus)

  • Heinz Läubli

    (University of Basel and University Hospital of Basel
    University Hospital Basel)

  • Christoph Hess

    (University of Basel and University Hospital of Basel
    University of Cambridge)

  • Alfred Zippelius

    (University of Basel and University Hospital of Basel
    University Hospital Basel)

Abstract

Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for T cell immunotherapies. T cells generated with this model resemble tumor-infiltrating exhausted T cells on a phenotypic and transcriptional level. Using a targeted pooled CRISPR-Cas9 screen and individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as a mediator of T cell exhaustion. Upon TCR/CD28 stimulation, deletion of SNX9 in CD8 T cells decreases PLCγ1, Ca2+, and NFATc2-mediated T cell signaling and reduces expression of NR4A1/3 and TOX. SNX9 knockout enhances memory differentiation and IFNγ secretion of adoptively transferred T cells and results in improved anti-tumor efficacy of human chimeric antigen receptor T cells in vivo. Our findings highlight that targeting SNX9 is a strategy to prevent T cell exhaustion and enhance anti-tumor immunity.

Suggested Citation

  • Marcel P. Trefny & Nicole Kirchhammer & Priska Auf der Maur & Marina Natoli & Dominic Schmid & Markus Germann & Laura Fernandez Rodriguez & Petra Herzig & Jonas Lötscher & Maryam Akrami & Jane C. Stin, 2023. "Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35583-w
    DOI: 10.1038/s41467-022-35583-w
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    References listed on IDEAS

    as
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