Synergy of adoptive T-cell therapy and intratumoral suicide gene therapy is mediated by host NK cells.
In situ tumor cell killing by the herpes simplex virus thymidine kinase (HSVtk) gene can effectively prime antitumor T-cell responses, at least in part through local induction of a pro-inflammatory environment. Therefore, we reasoned that tumor-associated HSVtk expression would significantly enhance the efficacy of adoptive T-cell transfer (ACT) of (tumor) antigen-specific T cells into tumor-bearing hosts. When B16ovaHSVtk tumors were treated with ganciclovir (GCV), along with suboptimal numbers of activated OT-1T cells, complete tumor regressions were observed where GCV, or ACT, alone was completely ineffective. To our surprise, analysis of regressing tumors showed no increases in intratumoral OT-1T cell trafficking. However, the intratumoral percentages of both OT-1 and endogenous natural killer (NK) cells were substantially increased over controls. Depletion of endogenous NK cells abrogated the efficacy of the combination therapy and reduced the percentages of interferon-gamma(IFNgamma)-secreting OT-1T cells in mice that received combined therapy to levels similar to those of control mice. These data suggest that even relatively low levels of gene transfer of suicide genes into tumors may have therapeutic value as an adjuvant for other T-cell therapies, by providing immunological signals that support T-cell activation and expansion in vivo.
Sanchez-Perez
L
L
Molecular Medicine Program, Mayo Clinic, Rochester, MN 55902, USA.
Gough
M
M
Qiao
J
J
Thanarajasingam
U
U
Kottke
T
T
Ahmed
A
A
Thompson
J M
JM
Maria Diaz
R
R
Vile
R G
RG
D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D003131:Combined Modality Therapy; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000235:genetics; D018139:Simplexvirus / Q000201:enzymology; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013937:Thymidine Kinase / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods
D000998:Antiviral Agents; D007371:Interferon-gamma; D010047:Ovalbumin; D013937:Thymidine Kinase; D015774:Ganciclovir