Production of interleukin-2 by EL4 tumor cells induces natural killer cell- and T-cell-mediated immunity.
Systemic administration of recombinant interleukin (rIL)-2 to cancer patients has met with limited clinical success since, despite significant antitumor effects, its use is associated with severe toxicity. Local production of IL-2 by IL-2 gene transfected tumor cells in murine model systems has been reported to induce specific immunity--devoid of toxicity--to the parental non-IL-2-producing tumor cells. We now report enhanced resistance in nonimmunized mice to murine EL4 thymoma cells, producing murine IL-2 following gene transfer (EL4pIL-2). This effect is mediated by activated natural killer (NK) cells, since we observed the same effect in nude mice but not in NK-depleted mice. Additionally, in mice repeatedly vaccinated with irradiated EL4pIL-2 cells, we observed immunity to challenge with a tumorigenic dose of EL4 cells transfected with a control vector, EL4p. EL4-specific cytotoxic T-lymphocytes (CTLs) were detected in these mice. Mice vaccinated with irradiated EL4p cells were less protected against challenge with a tumorigenic dose of EL4p cells. This study indicates that although some IL-2-producing autologous tumor cells elicit NK-mediated responses and not CTL responses upon inoculation, tumor-specific CTL responses are generated upon repeated vaccinations with these cells. This strategy has potential application for treating a wide variety of cancer patients with autologous IL-2 producing tumor cells.
Visseren
M J
MJ
Department of Immunohaematology, Academic Hospital Leiden, The Netherlands.
Koot
M
M
van der Voort
E I
EI
Gravestein
L A
LA
Schoenmakers
H J
HJ
Kast
W M
WM
Zijlstra
M
M
Melief
C J
CJ
D000818:Animals; D003602:Cytotoxicity, Immunologic; D018014:Gene Transfer Techniques; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000502:physiology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D013945:Thymoma / Q000276:immunology* / Q000628:therapy*; D014407:Tumor Cells, Cultured; D014612:Vaccines
D007376:Interleukin-2; D014612:Vaccines