Activation of the MDA-5–IPS-1 Viral Sensing Pathway Induces Cancer Cell Death and Type I IFN-Dependent Antitumor Immunity

Abstract

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.

Modulation of stress and immune response by Amblyomin-X results in tumor cell death in a horse melanoma model

“…CXCL10 probably stimulates monocytes, NK cells, and T-Cells or plays a role in modulating adhesion genes. Interferons type 1, IFNα and IFNβ, should be transcribed through one of the RLR pathway-branches -via TBK1, IRF3, and IRF7 -but we could not observe any transcript expression 46,47 . It is also important to highlight that TMEM173 (STING) was moderately expressed and not modulated, and PMAIP1 (NOXA), an important gene related to the Bortezomib pathway, was not transcribed.…”

Development of an IFNγ response‐related signature for predicting the survival of cutaneous melanoma

“…Among the four protective genes, UBE2L6 gene, encoding the ISG15 (IFN‐stimulated gene 15)‐conjugating enzyme UbcH8, was found to be correlated with apoptosis of cervical cancer 43 . Activation of IFIH1 (also known as MDA5) in tumors has been identified to facilitate re‐activation of tumor‐specific T cells which are otherwise functionally defective within the TME and to impede tumor‐induced immunosuppression in an IFN‐dependent manner 44,45 . The expression of GBP (Guanylate‐binding protein) has thus mostly been thought to be induced by IFNγ in various types of cells and is thought to help defend vertebrate cells against multiple invading pathogens and has antitumor activity 46 .…”

MDA5 Induces a Stronger Interferon Response than RIG-I to GCRV Infection through a Mechanism Involving the Phosphorylation and Dimerization of IRF3 and IRF7 in CIK Cells

“…The inhibition mechanism can be speculated from the distinct structures between MDA5 and RIG-I. As is well known that RIG-I but not MDA5 in a strictly autoinhibited conformation in the ligand-free state, the superabundant MDA5 in cytosol can lead to overactive immune response or apoptosis to threaten the cell survival ( 50 , 51 ). Therefore, to maintain the intracellular balance, MDA5 was downregulated by a present unknown mechanism when RIG-I overexpressed.…”