Elicitation of a systemic and protective anti-melanoma immune response by an IL-2-based vaccine. Assessment of critical cellular and molecular parameters.
We have established a model for the immunologic rejection of melanoma cells. Using a receptor-mediated, adenovirus-augmented gene delivery system (transferrinfection) we have shown that, upon transfection with an IL-2 gene construct, MHC class I+/class II- murine M-3 cells lose their tumorigenicity in both athymic and euthymic mice. More importantly, we found that these melanoma cells, which produce high levels of IL-2, can be used to induce a long-lasting anti-tumor immune response in syngeneic euthymic DBA/2 mice but not in athymic animals. This immune response, which can also be elicited by coadministration of nonmodified, irradiated M-3 cells and IL-2-transduced fibroblasts, results in the rejection of a subsequent challenge with M-3 cells or, in the elimination of preexisting M-3 cancer cell deposits. We found that transfer of T cell-enriched, but not of T cell-depleted, splenocytes from immunized mice conferred protection against M-3 cells, but not against unrelated KLN 205 cancer cells. Transfer of either CD4+ or CD8+ T cells led to only partial protection against challenge with wild-type M-3 cells. Our further observations that T cell-enriched, but not T cell-depleted splenocytes of immunized animals are capable of tumor-specific lytic activity and that this activity resides in the CD8+ cell population are compatible with the assumption that MHC class I-restricted T cell cytotoxicity is a biologically relevant effector mechanism in this model. That other mechanisms also contribute to melanoma cell destruction is evidenced by the presence of large numbers of macrophages and granulocytes in addition to T cells at the challenge sites of immunized mice.
Zatloukal
K
K
Research Institute of Molecular Pathology (I.M.P.), University of Vienna Medical School, Austria.
Schneeberger
A
A
Berger
M
M
Schmidt
W
W
Koszik
F
F
Kutil
R
R
Cotten
M
M
Wagner
E
E
Buschle
M
M
Maass
G
G
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D005434:Flow Cytometry; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D051379:Mice; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D011994:Recombinant Proteins; D014162:Transfection; D014612:Vaccines / Q000276:immunology*
D007376:Interleukin-2; D011994:Recombinant Proteins; D014612:Vaccines