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

• DOI: 10.1038/s41467-022-35583-w
• Publication Date: 2023-02-02T11:06:30Z
• Authors: Marcel P. Trefny; Nicole Kirchhammer; Priska Auf der Maur; Marina Natoli; Dominic Schmid; Markus Germann; Laura Fernandez R...; 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; Alfred Zippelius
• Keywords: 0301 basic medicine; Science; /13/106; /45/23; CD8-Positive T-Lymphocytes; Article; /38/91; /82/80; 03 medical and health sciences; Lymphocytes, Tumor-Infiltrating; Neoplasms; /692/308/575; /42/41; Humans; /692/4028/67/580; /14/19; 0303 health sciences; Q; article; /631/250/251; /96/21; T-Cell Exhaustion; 3. Good health; /13/31; /631/67/580; /13/95; /64/60; Immunotherapy; /82/1

AbstractTumor-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.