T cell exhaustion is driven by persistent antigen and stress signaling. In Science Immunology, Ford et al. report that a significant fraction of genes in tumor-infiltrating terminally exhausted PD1hiTIM3+CD8+ T cells maintain active chromatin histone modifications, but lack the corresponding gene transcription. Only 55% of active histone enhancers correlate with gene expression in terminally exhausted T cells, compared with 85% in progenitor exhausted PD1loTIM3−CD8+ T cells, with genes linked to T cell activation among those not expressed, despite many active histone marks. AP-1 motifs and the AP-1 transcription factor BATF are enriched in the active chromatin regions of tumor-infiltrating terminally exhausted T cells, but not in terminally exhausted T cells induced by chronic viral infection. CD137-targeted immunotherapy activates several AP-1 factors and increases the expression of active-chromatin, transcription-inactive genes in terminally exhausted T cells. Tumor-infiltrating terminally exhausted T cells, but not those induced by viral infection, also have a higher frequency of genes with bivalent chromatin, which is driven by hypoxia. Overexpression of the oxygen-insensitive histone demethylase Kdm6b increases transcription of bivalent genes and the antitumor activity of terminally exhausted T cells. As such, the tumor-infiltrating T cell exhaustion is shaped by the tumor environment.
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