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.
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
S J
SJ
Hall
M A
MA
Sanford
G
G
Atkinson
S H
SH
Chen
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