Publikation: Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy
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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 2+ , 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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TREFNY, Marcel P., Nicole KIRCHHAMMER, Priska AUF DER MAUR, Marina NATOLI, Dominic SCHMID, Markus GERMANN, Laura FERNANDEZ RODRIGUEZ, Petra HERZIG, Jérémie ROSSY, Alfred ZIPPELIUS, 2023. Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy. In: Nature Communications. Springer. 2023, 14(1), 86. eISSN 2041-1723. Available under: doi: 10.1038/s41467-022-35583-wBibTex
@article{Trefny2023-02-02Delet-66005, year={2023}, doi={10.1038/s41467-022-35583-w}, title={Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy}, number={1}, volume={14}, journal={Nature Communications}, author={Trefny, Marcel P. and Kirchhammer, Nicole and Auf der Maur, Priska and Natoli, Marina and Schmid, Dominic and Germann, Markus and Fernandez Rodriguez, Laura and Herzig, Petra and Rossy, Jérémie and Zippelius, Alfred}, note={Article Number: 86} }
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