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Trefny, Marcel P; Kirchhammer, Nicole; Auf der Maur, Priska; Natoli, Marina; Schmid, Dominic; Germann, Markus; Fernandez Rodriguez, Laura; Herzig, Petra; Lötscher, Jonas; Akrami, Maryam; Stinchcombe, Jane C; Stanczak, Michal A; Zingg, Andreas; Buchi, Melanie; Roux, Julien; Marone, Romina; Don, Leyla; Lardinois, Didier; Wiese, Mark; Jeker, Lukas T; Bentires-Alj, Mohamed; Rossy, Jérémie; Thommen, Daniela S; Griffiths, Gillian M; Läubli, Heinz; Hess, Christoph; Zippelius, Alfred
Nature communications, 02/2023, Volume: 14, Issue: 1Journal Article
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, Ca , 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.
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