Immunization with interleukin-2/interferon-gamma double cytokine-secreting allogeneic fibroblasts prolongs the survival of mice with melanoma.
LM mouse fibroblasts (H-2k) were modified for the expression of (antibody-defined) melanoma-associated antigens (MAA) and the secretion of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) (RLBA-IL-2/IFN-gamma cells). The cell construct was tested for its immunogenic properties in C57BL/6 mice (H-2b) with B16 melanoma. The results indicated that the survival of mice injected with a mixture of B16 cells and the modified, double cytokine-secreting fibroblasts was significantly longer than that of mice injected with B16 cells and LM cells modified for the expression of MAA and the secretion of IL-2 or IFN-gamma alone (RLBA-IL-2 or RLBA-IFN-gamma cells). Both natural killer/lymphokine-activated killer (NK/LAK) cells and Lyt-2.2 + CTLs with anti-melanoma cytotoxic activities were predominant in mice immunized with the double cytokine-secreting cells. B16 melanoma cells persisted in mice treated with RLBA-IL-2 cells (B16-R3). The B16-R3 cells were resistant to anti-melanoma effector cells from mice immunized with RLBA-IL-2 cells. The recurrent melanoma cells were deficient in the expression of MHC class I determinants. Class I expression by B16-R3 cells was increased if they were incubated in medium conditioned by the growth of IFN-gamma-secreting RLBA-IL-2/IFN-gamma or RLBA-IFN-gamma cells. After incubation, the sensitivity of B16-R3 melanoma cells to immune-effector cells from mice immunized with RLBA-IL-2 cells was restored. The survival of mice bearing low MHC class I-expressing B16-R3 cells, treated RLBA-IL-2/IFN-gamma cells, was determined. The treated animals survived significantly longer than mice with B16-R3 melanoma treated with RLBA-IL-2 cells. Similar results were obtained for mice with B16-R3 melanoma treated with RLBA-IFN-gamma cells. We postulate that immunization of mice with IL-2/IFN-gamma double cytokine-secreting cells stimulated multiple anti-melanoma effector mechanisms. Analogous to the enhanced therapeutic anti-tumour effects of combination chemotherapy, it was likely that treatment with a cellular immunogen engineered to stimulate more than one effector mechanism resulted in the elimination of larger numbers of tumour cells than treatment with an immunogen that stimulated a single effector mechanism alone.
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D001483:Base Sequence; D016827:CD8 Antigens / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D058950:Melanoma-Specific Antigens; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism
D000951:Antigens, Neoplasm; D016827:CD8 Antigens; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D007371:Interferon-gamma