An interferon-induced survival program in dedifferentiated cancer cells drives resistance to immuno-virotherapy

Oncolytic virotherapies are currently being explored to improve cancer immunotherapies. How the complex roles of interferons (IFNs) for host defenses against cancer cells and viruses shape responses to immuno-virotherapies is poorly understood. Here, we experimentally show that IFN-unresponsive melanoma cell subpopulations in heterogeneous tumors resist T-cell control but are efficiently eradicated with oncolytic virotherapy. Unexpectedly, T-cell immunity and viral oncolysis were abrogated by the emergence of dedifferentiated, IFN-responsive tumor cell subpopulations. On the molecular level, we discovered that the melanocyte master transcription factor MITF counter-regulates IFNα-mediated anti-viral responses in melanoma cells by dampening the upregulation of IFNα-stimulated anti-viral genes. A subset of these genes overlaps with the IFN-related DNA damage resistance signature (IRDS). The baseline expression of this subset in human melanoma cells is associated with non-response to immune checkpoint blockade in patients. Our results support current approaches targeting cancer cell dedifferentiation and chronic activation of IFN-signaling to advance immunotherapies.