Promoting protective antitumor immunity for cancer eradication

• Management of localized prostate cancer (PC) through surgical, radiation and chemotherapeutic approaches can be successful, but metastatic prostate cancer remains essentially incurable because no effective and safe treatment modality is available.
  
• Melanoma differentiation associated gene-5 (MDA-5), a type I interferon (IFN)-inducible gene, was originally cloned in human melanoma. This study indicates that MDA-5 can induce a direct tumoricidal or type I IFN-promoting effect in PC cells.
  
• This is the first demonstration of antitumor immunity induced by targeting the viral-sensing MDA-5 signaling pathway in prostate tumors. Therapeutic activation of MDA-5 at the tumor site is exploited to mobilize systemic innate and adaptive antitumor immune responses to eradicate metastatic PC.
  
• This MDA-5-targeting immunotherapy can be used either alone or in combination with other approaches to treat PC and other malignancies.
  

Counteracting the immunosuppressive tumor microenvironment (TME) and restoring immune effector cell functions remains a major challenge for successful cancer immunotherapy. In a study recently published in the journal of Cancer Research*, investigators in the VCU Institute of Molecular Medicine (VIMM) developed a novel strategy targeting the TME, which results in destruction of PC cells and concurrent induction of an antitumor immune response.

Melanoma differentiation associated gene-5 (MDA-5) was initially identified and cloned by Dr. Paul B. Fisher as a type I interferon (IFN)-inducible gene in human melanoma. Subsequent studies showed that MDA-5 represents a major innate immune receptor critically required for sensing viral pathogens and initiating an anti-viral host response involving production of type I IFNs. Dr. Fisher and his colleagues previously reported that forced expression of the MDA-5 gene kills cancer cells without harming normal cells. In this study involving a collaboration between Dr. Xiang-Yang (Shawn) Wang’s laboratory and Dr. Fisher, the investigators provide new insights into the biological impact of MDA-5 activation in cancer cells by defining the structural domains that confer a direct tumoricidal or type I IFN-promoting effect, which advances the understanding of the selective pro-apoptotic activity of MDA-5 in cancer cells, and not normal cells. A striking finding of this work is that intra-tumoral delivery of MDA-5 using an adenovirus results in regression of pre-established PCs and development of long-term protective antitumor immunity in immune competent mouse models. The mechanistic studies showed that this superior antitumor efficacy is primarily due to the activation of tumor-reactive cytotoxic T lymphocytes and/or natural killer cells, which is dependent on the type I IFN pathway in the TME. These findings underscore a previously unappreciated role of the MDA5-mediated viral sensing pathway in the induction of antitumor immunity, offering a new opportunity for therapeutic targeting of the immunosuppressive TME to restore systemic antitumor immunity for cancer eradication and prevention of relapse. Although this research was conducted in prostate cancer mouse models, it is believed that these data may have broad implications in the treatment of other malignancies and metastatic diseases. These promising preclinical results provide a strong scientific rationale to support potential translation of MDA-5-based immunotherapy. This study was supported in part by NIH grants CA175033, CA154708 (X.-Y. Wang), Department of Defense W81XWH-11-0480/0481, W81XWH-13-0409/0455 (P.B. Fisher and X.-Y. Wang), the National Foundation for Cancer Research (P.B. Fisher).