Induction of potent antitumor natural killer cell activity by herpes simplex virus-thymidine kinase and ganciclovir therapy in an orthotopic mouse model of prostate cancer.
Adenovirus-mediated transduction of the herpes simplex virus-thymidine kinase (HSV-tk) gene followed by ganciclovir is suspected to induce immune-mediated, systemic antitumor activities in the RM-1 mouse prostate cancer model (S. J. Hall et al., Int. J. Cancer, 70: 183-187, 1997). Although numerous investigators have also implied a role for the immune system in both local and systemic effects resulting from HSV-tk treatment, the candidate effector cell(s) mediating these activities are unknown. Fresh lymphocytes harvested from treated tumors (tumor-infiltrating lymphocytes) generated significant in vitro lytic activity against the parental cell line, RM-1, and an unrelated prostate cancer cell line. In vitro antibody and complement depletion of CD3+ T cells and natural killer (NK) cells from tumor-infiltrating lymphocytes indicated that NK cells were the dominant mediator of the observed tumor cell lysis. Concurrently, no cytotoxic T-cell activity was ascertained within splenocytes of treated mice. In vivo depletion of NK cells resulted in a 20% reduction in growth suppression within the primary tumor and complete abrogation of the inhibition of preestablished lung metastases. Depletion of T cells had no effect on either response. Here, we identify the presence of NK cells within adenovirus/HSV-tk- and ganciclovir-treated tumors, which serve to mediate both local and systemic antitumor activities in this model, and lay the mechanistic groundwork for further improvements in this gene therapy strategy.
Hall
S J
SJ
The Institute for Gene Therapy and Molecular Medicine, and Department of Urology, Mount Sinai School of Medicine, New York, New York 10029, USA. halls01@doc.mssm.edu
Sanford
M A
MA
Atkinson
G
G
Chen
S H
SH
D000256:Adenoviridae / Q000201:enzymology / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000494:pharmacology*; D015316:Genetic Therapy / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D017252:CD3 Complex; D013937:Thymidine Kinase; D015774:Ganciclovir