HSV oncolytic therapy upregulates interferon-inducible chemokines and recruits immune effector cells in ovarian cancer.
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.
Benencia
Fabian
F
Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
Courrèges
Maria C
MC
Conejo-García
José R
JR
Mohamed-Hadley
Alisha
A
Zhang
Lin
L
Buckanovich
Ronald J
RJ
Carroll
Richard
R
Fraser
Nigel
N
Coukos
George
G
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
D018925:Chemokines; D019707:Receptors, Chemokine; D007372:Interferons