The Transcription Factor IRF8 drives tumor-specific exhaustion in CD8 T cells

T-cell exhaustion is a hallmark of chronic infection and cancer and constitutes a major barrier for successful immunotherapies. In this study, we establish the central role of IRF8 as a transcription factor regulating tumor-induced T cell exhaustion. IRF8 is highly expressed in CD8 T cells in tumors but not during chronic infection, where the Irf8 locus is less accessible. Its expression depends on TCR stimulation but is altered in the presence of type I IFN. Overexpression of IRF8 strongly enforced T cell dysfunction while IRF8 knock-out in tumor specific CD8 T cells reduced TOX expression and ameliorated effector function by increasing IFNγ, GrzB and TNF production, resulting in a better tumor control. By comparing IRF8 to IRF2 and IRF4, we showed that the IRF family display some redundancy in the regulation of T cell exhaustion converging on TOX-dependent programs. Altogether, we established a new role for IRF8 as a tumor specific regulator of T cell function.