title: 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. 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 IFN production in mouse and human prostate cancer cells. This intrinsic dual activity of MDA-5 required the adaptor protein IFNβ promoter stimulator 1 (IPS-1, MAVS) and could be functionally uncoupled. MDA-5 lacking N-terminal caspase recruitment domains (CARD) engaged an intracellular death program in cancer cells but was unable to efficiently stimulate the expression of IFNβ. 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 preestablished 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 CARD-truncated MDA-5 mutant, silencing of IPS-1, and antibody blockade of the IFNα/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. Cancer Res; 76(8); 2166-76. ©2016 AACR.
authors.affiliation: Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.
authors.forename: Chunqing
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia. xywang@vcu.edu pbfisher@vcu.edu.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia. xywang@vcu.edu pbfisher@vcu.edu.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003673:Defective Viruses / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D000072640:Interferon-Induced Helicase, IFIH1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007370:Interferon Type I; C505371:MAVS protein, human; C452815:IFIH1 protein, human; D000072640:Interferon-Induced Helicase, IFIH1