Oncolytic Virotherapy: The Cancer Cell Side

Cell autonomous immunity genes mediate the multiple stages of anti-viral defenses, including recognition of invading pathogens, inhibition of viral replication, reprogramming of cellular metabolism, programmed-cell-death, paracrine induction of antiviral state, and activation of immunostimulatory inflammation. In tumor development and/or immunotherapy settings, selective pressure applied by the immune system results in tumor immunoediting, a reduction in the immunostimulatory potential of the cancer cell. This editing process comprises the reduced expression and/or function of cell autonomous immunity genes, allowing for immune-evasion of the tumor while concomitantly attenuating anti-viral defenses. Combined with the oncogene-enhanced anabolic nature of cancer-cell metabolism, this attenuation of antiviral defenses contributes to viral replication and to the selectivity of oncolytic viruses (OVs) towards malignant cells. Here, we review the manners by which oncogene-mediated transformation and tumor immunoediting combine to alter the intracellular milieu of tumor cells, for the benefit of OV replication. We also explore the functional connection between oncogenic signaling and epigenetic silencing, and the way by which restriction of such silencing results in immune activation. Together, the picture that emerges is one in which OVs and epigenetic modifiers are part of a growing therapeutic toolbox that employs activation of anti-tumor immunity for cancer therapy.