The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity

Type I Interferons (IFN-I) stimulate pro-inflammatory programs critical for immune activation, but also induce immune-suppressive feedback circuits that contribute to the failure of cancer control. Yet, how IFN-Is differentially induce these opposing programs remains enigmatic. We establish that the transcription factor Interferon Regulatory Factor 2 (IRF2) is a central feedback molecule attenuating IFN signaling and driving CD8 T cell exhaustion in the tumor microenvironment. IRF2 inhibits CD8 T cell effector function in response to sustained interferon signaling by programming T cell exhaustion. Lineage-specific deletion of IRF2 limits CD8 T cells exhaustion to maintain effector functions, thereby enabling long-term tumor control, and increased responsiveness to immune-checkpoint and adoptive cell therapies. Long-term tumor control by IRF2-deficient CD8 T cells is dependent on continuous integration of both IFN-I and IFN? signals, which in the absence of IRF2, potentiate sustained effector function instead of exhaustion. Thus, IRF2 redirects IFN signalling to drive T cell exhaustion and prevent tumor control. Overall design: For AB-Seq experiment, MC38 Tumor-infitrating CD8 T cells from WT (Tumor WT), Irf2-/- (Tumor IRF2KO) mice. For scATAC-Seq experiment, MC38 Tumor-infitrating CD8 T cells from WT (Tumor WT), Irf2-/- (Tumor Irf2-/-) mice, as well as MC38 Tumor-infitrating CD8 T cells from mice that only lack IRF2 expression in the CD8 T cells (termed Tumor CD8-IRF2cKO mice) together with their controls Tumor CD8-IRF2cWT). For CUT&Tag - Naive isolated CD8+ T cells were isolated and invitro activated using anti-CD3 and Anti-CD28 and subjecte to either anti-IRF2 or IgG antibodies.