title: Efficient suicide gene therapy of transduced and distant untransduced ovary tumors is correlated with significant increase of intratumoral T and NK cells.
abstract: Gene therapy using herpes simplex type 1 thymidine kinase gene (HSV1-TK) transfer followed by ganciclovir (GCV) treatment has revealed an important intratumoral and regional bystander effect that is at least partly immune-mediated. The aim of this work was to study the modifications of T lymphocyte subpopulations in a model of distant bystander effect occurring between ovary tumors. Bilateral ovarian tumors were generated in 21 WKY rats by injection in the ovarian pouch of either parental or HSV1-TK-expressing DWA-OC-1 ovarian cancer cells. After 14 days, rats were treated for two weeks with GCV (75 mg/kg x 2/d) or saline. All rats were killed at day 29 for pathological examination. The tumor-infiltrating mononuclear cells were analyzed by semi-quantitative immunohistochemistry. As compared to rats receiving saline, GCV-treated animals exhibited a complete disappearance of the HSV1-TK+ tumors with residual fibrotic scars (ovary weights: 0.46 +/- 0.4 g vs 10.11 +/- 1.5 g, P < 0.001). Interestingly, the contralateral HSV1-TK negative tumor showed a significant regression (12.39 +/- 1.93 g vs 22.24 +/- 237 g, P < 0.014). Furthermore, a lower incidence of tumoral ascitis was found in the GCV-receiving group (20% vs 90% P < 0.02). Within both TK- and TK+ tumors, there was a significant increase of CD4+, CD8+ and NK cells in the GCV-treated group compared to the saline-treated group. This study thus indicates that a distant bystander effect not only acts between close tumors within a given organ such as the liver, but also between more distant tumors in the peritoneal cavity. This effect is associated with significant infiltration of the tumor by immune system cells, supporting the notion that the distant bystander effect is immune-mediated.
authors.affiliation: Laboratoire de Recherche Chirurgicale, H pital Cochin, Université Paris V, France.
authors.forename: H J
authors.initials: HJ
authors.lastname: Nagy
authors.forename: Y
authors.initials: Y
authors.lastname: Panis
authors.forename: M
authors.initials: M
authors.lastname: Fabre
authors.forename: C
authors.initials: C
authors.lastname: Engelmann
authors.forename: O
authors.initials: O
authors.lastname: Soubrane
authors.forename: D
authors.initials: D
authors.lastname: Houssin
authors.forename: D
authors.initials: D
authors.lastname: Klatzmann
mesh_terms: D000818:Animals; D005260:Female; D015316:Genetic Therapy; D018259:Herpesvirus 1, Human / Q000235:genetics; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000473:pathology*; D018655:Lymphocyte Count; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar; D013601:T-Lymphocytes / Q000473:pathology*; D013937:Thymidine Kinase / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D013937:Thymidine Kinase