Inhibition of tumor growth by targeting the MDA5-IPS-1 pathway requires coordinated induction of cancer cell death and immune activation (TUM2P.891)

Abstract

Abstract Melanoma differentiation-associated antigen 5 (MDA5), a cytosolic innate pattern recognition receptor for sensing double-stranded RNA, functions as a first line of defense against viral infection. Here we report that ectopic expression of MDA5, mediated by a replication incompetent adenovirus (Ad.Mda5), results in prostate cancer cell death and concomitant innate immune activation, e.g., production of type I interferons (IFNs). IFN-β promoter stimulator (IPS)-1, a downstream adaptor protein, is critical for MDA5-stimulated cancer cell apoptosis and type I IFN response. While MDA5-regulated IFN regulatory factor 3-IFN-β signaling cascade remains intact in nontransformed normal cells, these cells are less sensitive to MDA5-induced apoptosis compared with cancer cells. Intriguingly, intratumoral delivery of Ad.Mda5 preferentially remodels the tumor environment toward Th1 polarization, indicated by marked elevation of cytokine IFN-β, IL-12, and IFN-gamma. As a result, in situ overexpression of MDA5 leads to strong suppression of established mouse prostate tumors, which is associated with activation of natural killer (NK) cells and cytotoxic CD8+ T lymphocytes. Genetic ablation or antibody neutralization reveals that antitumor effect of MDA5 therapy depends on IPS1, IFN-β, and IL-12. Therefore, the intrinsic capabilities of ‘danger’ sensing MDA-5 in simultaneously promoting cancer cell death and immune augmentation may be exploited to develop novel cancer therapeutics.