Tumour cell vaccines that secrete interleukin-2 (IL-2) and interferon gamma (IFN gamma) are recognised by T cells while resisting destruction by natural killer (NK) cells.
The inoculation into mice of genetically engineered tumour cells that secrete IL-2 or IFN gamma results in rejection, while unmodified parental tumour cells grow progressively. In vivo studies demonstrated synergy between IL-2 and IFN gamma leading to the rejection of the transduced tumour cells. IL-2 is required for T cell proliferation and differentiation. IFN gamma induced the upregulation of MHC class I molecules that present peptides to CD8+ T cells. Furthermore, IFN gamma can correct defects in antigen processing. Thus, for T cells, IL-2/IFN gamma-secreting double cytokine tumour cell vaccines might serve as class I+ peptide/antigen presenting depots for developing effector cells. In contrast to T cells, NK cells exert spontaneous killing and kill class I+ targets less well than those that are class I-. For this reason, they may actually have a detrimental effect by destroying a class I+ tumour cell vaccine before adequate T cell stimulation occurs. Based upon this rationale, we tested the hypothesis that an unrecognised benefit of increased class I expression by tumour cells in response to IFN gamma secretion would be to enable cytokine-secreting vaccine cells to resist destruction by NK cells. Our results demonstrated that T cells recognised tumour cells secreting IFN gamma better than those secreting IL-2. NK cells, in contrast, were inhibited by tumour cells that secreted IFN gamma, but not by those that secreted IL-2. The findings suggest that, in addition to upregulating adhesion molecules, MHC molecules, and correcting defects in antigen presentation pathways, IFN gamma secretion may protect tumour cell vaccines from early NK-mediated destruction, keeping them available for T cell priming.
Zier
K S
KS
Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Gansbacher
B
B
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005354:Fibrosarcoma / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D016233:Immunotherapy, Active; D007371:Interferon-gamma / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D015815:Cell Adhesion Molecules; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D007371:Interferon-gamma