Journal Article

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

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

2023

Overview

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. The efficacy of T-cell-based cancer immunotherapies can be compromised by T cell exhaustion. Here the authors develop a human ex vivo exhaustion model and, based on a CRISPR-Cas9 screen, identify SNX9 as a regulator of T cell exhaustion, showing that SNX9 knockout is associated with improved T cell function and anti-tumor activity in preclinical cancer models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/31 / 13/95 / 14/19 / 38/91 / 42/41 / 45/23 / 631/250/251 / 631/67/580 / 64/60 / 692/308/575 / 692/4028/67/580 / 82/1 / 82/80 / 96/21 / Anticancer properties / Antigens / Antitumor agents / Calcium ions / Cancer / Cancer immunotherapy / CD28 antigen / CD8 antigen / CD8-Positive T-Lymphocytes / Cell signaling / Chimeric antigen receptors / CRISPR / Deletion / Effectiveness / Humanities and Social Sciences / Humans / Immunotherapy / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating / Memory cells / multidisciplinary / Neoplasms / Nexin / Science / Science (multidisciplinary) / Stimulation / T cell receptors / T-Cell Exhaustion / Tumor-infiltrating lymphocytes / Tumors / γ-Interferon