Efficient suicide gene therapy of transduced and distant untransduced ovary tumors is correlated with significant increase of intratumoral T and NK cells

Gene therapy using herpes simplex type 1 thymidine kinase gene (HSV1-TK) tr ansfer followed by ganciclovir (GCV) treatment has revealed an important in tratumoral and regional bystander effect that is at least partly immune-med iated. The aim of this work was to study the modifications of T lymphocyte subpopulations in a model of distant bystander effect occurring between ova ry tumors, Bilateral ovarian tumors were generated in 21 WKY rats by inject ion 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 G CV (75 mg/kg x 2/d) or saline. All rats were killed at day 29 for pathologi cal examination. The tumor-infiltrating mononuclear cells were analyzed by semi-quantitative immunohistochemistry. As compared to rats receiving saline, GCV-treated animals exhibited a compl ete disappearance of the HSV1-TK+ tumors with residual fibrotic scars (ovar y weights: 0.46 +/- 0.4 g vs 10.11 +/- 1.5 g, P < 0.001). Interestingly, th e 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 incidenc e 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 C D4+, CD8+ and NK cells in the GCV-treated group compared to the saline-trea ted group. This study thus indicates that a distant bystander effect not on ly acts between close tumors within a given organ such as the liver, but al so between more distant tumors in the peritoneal cavity. This effect is ass ociated with significant infiltration of the tumor by immune system cells, supporting the notion that the distant bystander effect is immune-mediated. (C) 2000 Editions scientifiques et medicales Elsevier SAS.