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

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 PLC.1, Ca2+, and NFATc2-mediated T cell signaling and reduces expression of NR4A1/3 and TOX. SNX9 knockout enhances memory differentiation and IFN. 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.

Automated summary

In this study, a human antigen-specific ex vivo model was used to explore new therapeutic options for T cell immunotherapies. The protein SNX9 was identified as a mediator of T cell exhaustion, and its knockout resulted in enhanced memory differentiation and function of adoptively transferred T cells, improving anti-tumor efficacy of chimeric antigen receptor T cells in vivo.