Interferons and the Immunogenic Effects of Cancer Therapy

Much of our understanding on resistance mechanisms to conventional cancer therapies such as chemotherapy and radiation has focused on cell intrinsic properties that antagonize the detrimental effects of DNA and other cellular damage. However, it is becoming clear that the immune system and/or innate immune signaling pathways can integrate with these intrinsic mechanisms to profoundly influence treatment efficacy. In this context, recent evidence indicates that interferon (IFN) signaling has an important role in this integration by influencing immune and intrinsic/non-immune determinants of therapy response. However, IFN signaling can be both immunostimulatory and immunosuppressive, and the factors determining these outcomes in different disease settings are unclear. Here I discuss the regulation and molecular events in cancer that are associated with these dichotomous functions.

TrendsGenotoxic cancer therapy can instigate immune activation, thus enhancing the response to genotoxic therapy. Response to chemotherapy and radiation can require IFN signaling and T cell activation. Combining conventional cancer therapies with immune checkpoint blockade can work cooperatively to promote tumor response.ISGs are widely expressed in human cancers and can predict therapy response. Various human cancers display an ISG signature indicative of IFN signaling; however, its expression can be associated with good response or poor response to cancer therapy.IFN signaling can regulate immune-suppressive events. Evidence from pathogen infection and cancer models suggests that IFNs can stimulate or suppress immune responses.RNA and DNA can function as DAMPs, activating IFN signaling in cancer. In a sterile tumor microenvironment, cancer cells can activate RNA and DNA pattern recognition receptors to induce IFN signaling and ISG expression.Timing and duration of IFN signaling and phosphorylation status of STAT1 can influence the immune response. After IFN-induced phosphorylated STAT1 declines, unphosphorylated STAT1 increases and can transcriptionally regulate a subset of ISGs associated with persistent viral infection and cancer therapy resistance.