Activation of the MDA5-IPS1 viral sensing pathway induces cancer cell death and type I interferon-dependent antitumor immunity

Melanoma differentiation-associated gene 5 (MDA-5, IFIH1), a cytosolic innate pattern recognition receptor, functions as a first line of defense against viral infection by sensing double-stranded RNA (dsRNA). Ectopic expression of MDA-5 has been shown to induce cancer cell death, but the mechanism of action by which MDA-5 exerts these cytotoxic effects is unclear. Here, we demonstrate that ectopic expression of MDA-5 via replication incompetent adenovirus (Ad.Mda-5) initiates multiple signaling cascades, culminating in cytotoxicity and type I interferon (IFN) production in mouse and human prostate cancer cells. This intrinsic dual activity of MDA-5 required the adaptor protein IFN-β promoter stimulator 1 (IPS-1, MAV) and could be functionally uncoupled. MDA-5 lacking N-terminal caspase-recruitment domains (CARDs) engaged an intracellular death program in cancer cells, but was unable to efficiently stimulate expression of IFN-β. In contrast to cancer cells susceptible to MDA-5-mediated cytotoxicity, normal cells were highly resistant and instead developed a robust type I IFN response. Strikingly, intratumoral delivery of Ad.Mda-5 led to regression of pre-established prostate cancers and development of long-lasting antitumor immune memory, which was primarily attributed to the activation of tumor-reactive cytotoxic T lymphocytes and/or natural killer cells. Using the CARDs-truncated MDA-5 mutant, silencing of IPS-1, and antibody blockade of the IFN-α/β-receptor, we further demonstrate that type I IFN signaling was crucial for in situ MDA-5-induced protective antitumor immunity. Therefore, deliberately targeting the evolutionarily conserved MDA-5-IPS-1 antiviral pathway in tumors can provoke parallel tumoricidal and immunostimulatory effects that bridge innate and adaptive immune responses for the therapeutic treatment of cancer.

from Cancer via ola Kala on Inoreader http://ift.tt/21csuFq
via IFTTT