title: HSV oncolytic therapy upregulates interferon-inducible chemokines and recruits immune effector cells in ovarian cancer.
abstract: Cooperation between oncolytic herpes simplex virus (HSV) and host effector immune mechanisms has been previously described. In the present study, we investigated the mechanism underlying such cooperation in a murine syngeneic model of ovarian carcinoma. Therapeutic administration of HSV-1716, a replication-restricted mutant, resulted in significant reduction of tumor growth and a significant survival advantage. Intratumoral injection of HSV-1716 induced expression of IFN-gamma, MIG, and IP-10 in the tumor. This was accompanied by a significant increase in the number of tumor-associated NK and CD8+ T cells expressing CXCR3 and CD25. Ascites from HSV-1716-treated animals efficiently induced in vitro migration of NK and CD8+ T cells, which was dependent on the presence of MIG and IP-10. Murine monocytes and dendritic cells (DCs) were responsible for the production of MIG and IP-10 upon HSV-1716 infection. In monocytes, this was partially abrogated by neutralizing antibodies against IFN-alpha and -beta, thus indicating a role for type-1 IFNs in the reported effect. Human ovarian carcinomas showed high numbers of monocytes and DCs. Upon HSV-1716 infection, human monocyte-derived DCs produced large amounts of IFN-gamma and upregulated MIG and IP-10 expression. These results indicate that HSV-1716 induces an inflammatory response that may facilitate antitumor immune response upon oncolytic therapy.
authors.affiliation: Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
authors.forename: Fabian
authors.initials: F
authors.lastname: Benencia
authors.forename: Maria C
authors.initials: MC
authors.lastname: Courrèges
authors.forename: José R
authors.initials: JR
authors.lastname: Conejo-García
authors.forename: Alisha
authors.initials: A
authors.lastname: Mohamed-Hadley
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Buckanovich
authors.forename: Richard
authors.initials: R
authors.lastname: Carroll
authors.forename: Nigel
authors.initials: N
authors.lastname: Fraser
authors.forename: George
authors.initials: G
authors.lastname: Coukos
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D018925:Chemokines / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007372:Interferons / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000628:therapy; D019707:Receptors, Chemokine; D018139:Simplexvirus / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D018925:Chemokines; D019707:Receptors, Chemokine; D007372:Interferons