Extended Data Fig. 10: Comparison of functional TOX^low OT1 and dysfunctional TOX knockout T cells in tumours with proposed model on the role of TOX in tumour-specific CD8 T cell exhaustion and dysfunction.

a, DEGs of the TAG versus OT1 comparison (see Fig. 2) were compared with DEGs of the wild-type versus TOX-knockout comparison (see Fig. 4). There were 389 genes identified to be significantly differentially expressed in both (WT vs KO and TAG vs OT1). b, Heat map of normalized expression values (log₂(counts per million)) across all samples (colour corresponds to z-scores) for these 389 genes. Selected genes of interest are highlighted. c, Proposed model on the role of TOX in tumour-specific CD8 T cell exhaustion and dysfunction. Top, antigen-specific T cells in solid tumours are continuously triggered with tumour antigen. Chronic TCR stimulation leads to NFAT-mediated expression of TOX. TOX induces a transcriptional and epigenetic program and phenotype associated with exhaustion, including the expression of numerous inhibitory receptors (for example, PD-1, LAG-3, 2B4, CD39 and CD38) and downregulation of transcription factors (such as TCF-1). The TOX-mediated exhaustion program prevents T cells from overactivation or overstimulation and activation-induced cell death. Bottom, TOX-deficient T cells do not upregulate inhibitory receptors, become overstimulated or overactivated, and eventually undergo activation-induced cell death. Despite their non-exhausted phenotype, TOX-deficient T cells are dysfunctional.