In cancer, interferon-γ (IFN-γ) signaling can induce expression of the checkpoint ligand PD-L1. In Cell, Benci et al. investigate whether interferons can induce tumor resistance beyond upregulation of PD-L1. In a melanoma model, prolonged IFN-γ signaling in vitro and in vivo induces adaptive resistance to immunotherapy, which is maintained by both type I interferons and type II interferons. Persistent IFN-γ stimulation increases the expression and genome occupancy of the transcription factor STAT1 in melanoma cell lines and induces an epigenetic profile similar to that of resistant tumors, characterized by high expression of inhibitory receptors, such as PD-L1, TIM3, LAG3 and galectin-9, and of cancer-associated products of interferon-stimulated genes, such as IFIT1 and Mx1. Blocking interferon signaling or deletion of receptors for type I and type II interferons 'rescues' the tumor response to PD-1- or CTLA-4-blockade therapy. In patients, high expression of IFIT3 and Mx1 correlates with progression after PD-1-blockade therapy.

Cell 167, 1540–1554 (2016)