title: Gemcitabine enhances the efficacy of reovirus-based oncotherapy through anti-tumour immunological mechanisms.
abstract: BACKGROUND
  Reovirus preferentially infects and kills cancer cells and is currently undergoing clinical trials internationally. While oncolysis is the primary mode of tumour elimination, increasing evidence illustrates that reovirus additionally stimulates anti-tumour immunity with a capacity to target existing and possibly relapsing cancer cells. These virus-induced anti-tumour immune activities largely determine the efficacy of oncotherapy. On the other hand, anti-viral immune responses can negatively affect oncotherapy. Hence, the strategic management of anti-tumour and anti-viral immune responses through complementary therapeutics is crucial to achieve the maximum anti-cancer benefits of oncotherapy.
  
  
  METHODS
  Intra-peritoneal injection of mouse ovarian surface epithelial cells (ID8 cells) into wild-type C57BL/6 mice was treated with a therapeutic regimen of reovirus and/or gemcitabine and then analysed for prolonged survival, disease pathology, and various immunological parameters. Furthermore, in vitro analyses were conducted to assess apoptosis, viral spread, and viral production during reovirus and/or gemcitabine treatment.
  
  
  RESULTS
  We demonstrate that reovirus and gemcitabine combination treatment postpones peritoneal carcinomatosis development and prolongs the survival of cancer-bearing hosts. Importantly, these anti-cancer benefits are generated through various immunological mechanisms, including: (1) inhibition of myeloid-derived suppressor cells recruitment to the tumour microenvironment, (2) downmodulation of pro-MDSC factors, and (3) accelerated development of anti-tumour T-cell responses.
  
  
  CONCLUSIONS
  The complementation of reovirus with gemcitabine further potentiates virus-initiated anti-cancer immunity and enhances the efficacy of oncotherapy. In the context of ongoing clinical trials, our findings represent clinically relevant information capable of enhancing cancer outcomes.
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: S A
authors.initials: SA
authors.lastname: Gujar
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Clements
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Dielschneider
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Helson
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Marcato
authors.affiliation: 1] Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada [2] Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: P W K
authors.initials: PW
authors.lastname: Lee
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D050130:Oncolytic Virotherapy / Q000379:methods*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D012087:Reoviridae / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D014779:Virus Replication / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine