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

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. Stinchcombe, Michal A. Stanczak, Andreas Zingg, Melanie Buchi, Julien Roux, Romina Marone, Leyla Don, Didier Lardinois, Mark Wiese, Lukas T. Jeker, Mohamed Bentires-Alj, Jérémie Rossy, Daniela S. Thommen, Gillian M. Griffiths, Heinz Läubli, Christoph Hess and Alfred Zippelius ()
Additional contact information
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
Romina Marone: University of Basel and University Hospital of Basel
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
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
Gillian M. Griffiths: Cambridge Institute for Medical Research, Biomedical Campus
Heinz Läubli: University of Basel and University Hospital of Basel
Christoph Hess: University of Basel and University Hospital of Basel
Alfred Zippelius: University of Basel and University Hospital of Basel

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35583-w

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