title: Multifaceted therapeutic targeting of ovarian peritoneal carcinomatosis through virus-induced immunomodulation.
abstract: Immunosuppression associated with ovarian cancer (OC) and resultant peritoneal carcinomatosis (PC) hampers the efficacy of many promising treatment options, including immunotherapies. It is hypothesized that oncolytic virus-based therapies can simultaneously kill OC and mitigate immunosuppression. Currently, reovirus-based anticancer therapy is undergoing phase I/II clinical trials for the treatment of OC. Hence, this study was focused on characterizing the effects of reovirus therapy on OC and associated immune microenvironment. Our data shows that reovirus efficiently killed OC cells and induced higher expression of the molecules involved in antigen presentation including major histocompatibility complex (MHC) class I, β2-microglobulin (β2M), TAP-1, and TAP-2. In addition, in the presence of reovirus, dendritic cells (DCs) overcame the OC-mediated phenotypic suppression and successfully stimulated tumor-specific CD8+ T cells. In animal studies, reovirus targeted local and distal OC, alleviated the severity of PC and significantly prolonged survival. These therapeutic effects were accompanied by decreased frequency of suppressive cells, e.g., Gr1.1+, CD11b+ myeloid derived suppressor cells (MDSCs), and CD4+, CD25+, FOXP3+ Tregs, tumor-infiltration of CD3+ cells and higher expression of Th1 cytokines. Finally, reovirus therapy during early stages of OC also resulted in the postponement of PC development. This report elucidates timely information on a therapeutic approach that can target OC through clinically desired multifaceted mechanisms to better the outcomes.
authors.affiliation: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Shashi
authors.initials: S
authors.lastname: Gujar
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dielschneider
authors.forename: Derek
authors.initials: D
authors.lastname: Clements
authors.forename: Erin
authors.initials: E
authors.lastname: Helson
authors.forename: Maya
authors.initials: M
authors.lastname: Shmulevitz
authors.forename: Paola
authors.initials: P
authors.lastname: Marcato
authors.forename: Da
authors.initials: D
authors.lastname: Pan
authors.forename: Lu-Zhe
authors.initials: LZ
authors.lastname: Pan
authors.forename: Dae-Gyun
authors.initials: DG
authors.lastname: Ahn
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Alawadhi
authors.forename: Patrick W K
authors.initials: PW
authors.lastname: Lee
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002277:Carcinoma / Q000628:therapy*; D045744:Cell Line, Tumor; D060833:Cellular Microenvironment; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology / Q000821:virology; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D056747:Immunomodulation; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D050130:Oncolytic Virotherapy / Q000379:methods*; D010051:Ovarian Neoplasms / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000628:therapy*; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D012087:Reoviridae / Q000235:genetics* / Q000276:immunology
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; C073119:TAP1 protein, human; C071692:TAP2 protein, human