422. Harnessing Immunogenic Cell Death to Potentiate the Oncolytic Effect of ORFV Infection in Murine Cancer Cells
Authors: Jacob P. vanVloten, Lisa A. Santry, Jondavid de Jong, Byram W. Bridle, Sarah K. Wootton
Journal: Molecular Therapy (2016)

Immunogenic cell death (ICD) is a recently uncovered phenomenon in which cells committed to death undergo a distinct cascade of events that culminate in the release of factors that alert the immune system. This is in contrast to conventional apoptosis, which is immunologically silent. Studies investigating the effect of anthracycline-induced cancer cell death demonstrated that translocation of calreticulin (an endoplasmic reticulum protein) to the cell surface and extracellular secretion of ATP and high-mobility group box 1 (HMGB1; a nuclear DNA-binding protein) drive immunogenicity1Kroemer G. Galluzzi L. Kepp O. Zitvogel L. Immunogenic cell death in cancer therapy.Annu. Rev. Immunol. 2013; 31: 51-72Crossref PubMed Scopus (1950) Google Scholar, 2Obeid M. et al.Calreticulin exposure dictates the immunogenicity of cancer cell death.Nat. Med. 2007; 13: 54-61Crossref PubMed Scopus (2160) Google Scholar. Surface calreticulin acts as a pro-phagocytic signal, leading to increased processing of tumor antigens by dendritic cells. ATP interacts with receptors on immune cells and has a strong chemotactic effect. Outside of the nucleus, HMGB1 functions as either a chemokine or pro-inflammatory cytokine depending on its oxidation state. In the context of ICD, calreticulin, ATP and HMGB1 enhance the immune response to tumor antigens and improve the efficacy of anti-cancer therapies in murine models. Current research is beginning to delineate the important cellular events that dictate the ICD response in cancer cells2Obeid M. et al.Calreticulin exposure dictates the immunogenicity of cancer cell death.Nat. Med. 2007; 13: 54-61Crossref PubMed Scopus (2160) Google Scholar, 3Panaretakis T. et al.Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death.EMBO J. 2009; 28: 578-590Crossref PubMed Scopus (583) Google Scholar, 4Kepp O. et al.Crosstalk between ER stress and immunogenic cell death.Cytokine Growth Factor Rev. 2013; 24: 311-318Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar. Importantly, several of these pathways overlap with the cellular response to viral infection5Kepp O. et al.Viral subversion of immunogenic cell death.Cell Cycle. 2009; 8: 860-869Crossref PubMed Scopus (54) Google Scholar and numerous viruses have indeed been shown to induce ICD in infected cancer cells. Parapoxivirus ovis (ORFV) is a poxvirus and veterinary pathogen causing transmissible pustular dermatitis in sheep. ORFV is able to infect multiple cancer cell types and has demonstrated impressive efficacy in in vivomodels, largely due to its high immunogenicity6Rintoul J. et al.ORFV: a novel oncolytic and immune stimulating Parapoxvirus therapeutic.Mol. Ther. 2012; 20: 1148-1157Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar. To elucidate the cause of ORFV immunogenicity, we investigate the relationship between ORFV infection and the ICD response in cancer cells by analyzing the three hallmarks: calreticulin surface translocation and ATP and HMGB1 release. Multiple murine cancer cells lines were investigated, encompassing established models of mammary, ovarian, prostate and skin cancer. Additionally, the ability of ORFV to induce ICD was compared to that of other clinically relevant oncolytic viruses including vaccinia (JX-594), Maraba (MG1) and Newcastle disease virus (NDV/F3aa).