2.2.1. RAS-Mediated Regulation of Immune Transcription Factors

In accord with oncogene-mediated regulation of gene expression programs, a critical mechanism by which they modify immune/antiviral functions of tumor cells is through regulation of the expression of immunity-related transcription factors. In HRAS transformed murine fibroblasts, and RAS-transformed human cancer cells, MEK-ERK signaling was shown to negatively regulate IRF-1-dependent transcription of IRF1 and STAT2 [13,14], thus hampering IFN responses, and supporting the replication of oncolytic vesicular stomatitis virus (VSV). In addition to immune-related functions (e.g., as antiviral gene, master regulator of acute inflammation, and main effector of IFNγ signaling), IRF1 was also characterized as a tumor-suppressor [15–19]. Thus, IRF1 inhibition by RAS-MEK is predicted to concomitantly promote tumorigenicity, alter the interactions between tumor- and immune cells and enhance the susceptibility of cancer cells to OVs. Of note, the antagonism of IRF1 function by mitogenic pathways is not restricted to cancer settings. For example, in airway epithelial cells, influenza A virus (IAV) and rhinovirus activate the epidermal growth factor receptor (EGFR, [20])—an upstream activator of the RAS/RAF/MEK/ERK pathway [21]. Activated EGFR diminishes both IRF1 expression and induction of IFN-λ production, thus increasing viral infection. Oncogenic KRAS was shown to inhibit the expression of STAT1, STAT2 and IRF9 (members of the ISGF3 transcription-promoting complex); thus, hampering the basal and IFN-induced expression of ISGs in colorectal cancer cell lines [22]. This effect was proposed to be mediated (at least in part) through the PI3K pathway. Moreover, a recent study employing a murine model of colorectal cancer combining oncogenic KRAS expression with conditional null alleles of adenomatous polyposis coli (*APC*) and *TRP53*, identified repression of IRF2 as a key mechanism for KRAS-induced immune-suppression in colorectal cancer [23]. It should be noted that the roles of IRF2 in cancer are controversial. Thus, while IRF2 expression is downregulated in many different tumor types [24] suggesting potential tumor suppressor roles, other studies proposed pro-tumorigenic functions for IRF2, including via antagonism of IRF1 functions [15,25]. Similarly, while IRF2 was proposed to antagonize IRF1 antiviral responses [26], more recent studies suggest complementary roles for IRF1 and IRF2 in IFN-induced gene expression.
