title: Cytokines alter target cell susceptibility to lysis: I. Evaluation of non-major histocompatibility complex-restricted effectors reveals differential effects on natural and lymphokine-activated killing.
abstract: Interferon-gamma (IFN) and tumor necrosis factor-alpha (TNF) were examined for their ability to enhance major histocompatibility complex (MHC) expression on a variety of human tumor and normal tissue targets. Enhanced expression of MHC correlated with decreased target susceptibility to lysis by fresh peripheral blood mononuclear cells (PBMCs) and IL-2-augmented PBMCs (aPBL) but not as clearly with cells with lymphokine-activated killer (LAK) activity. These studies revealed maximal MHC enhancement after 48-72 h of incubation in IFN. Resistance to lysis by natural killer (NK) cells was best demonstrated after 72 h. Further, IFN and TNF were synergistic in their effects on MHC expression and induction of resistance of the cultured leukemias K562 and Molt-4 to aPBL effectors. Conversely, LAK susceptibility was usually unaltered after target IFN and TNF treatment. Incubation of fibroblasts and vascular endothelial cells with IFN also consistently resulted in MHC class I enhancement and resistance to NK lysis, whereas LAK susceptibility was variably affected. The brief incubation of fresh PBL in IL-2 (4-6 h) resulted in effectors highly lytic toward cultured cells, but with no activity against fresh tumor. Cultured cell lines treated with IFN and TNF were rendered relatively resistant to lysis by these activated cells. Fresh tumor MHC expression and LAK susceptibility was unchanged after IFN incubation. Additionally, there was no correlation between the level of MHC class I or class II expression and LAK susceptibility to any fresh, uncultured melanoma studied. These data suggest that LAK effectors possess different mechanisms of tumor recognition or lysis than cells with NK activity or cells briefly incubated (4-6 h) in IL-2. The ability of tumor-infiltrating lymphocytes to lyse the cultured autologous tumor target was markedly increased by preincubation of the targets with IFN and TNF. Finally, it appears that IL-2 treatment and the resultant endogenous production of IFN by T-lymphocytes should not adversely affect tumor susceptibility to current immunotherapy using IL-2.
authors.affiliation: Surgery Branch, National Cancer Insitute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: E A
authors.initials: EA
authors.lastname: Wiebke
authors.forename: M C
authors.initials: MC
authors.lastname: Custer
authors.forename: S A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: M T
authors.initials: MT
authors.lastname: Lotze
mesh_terms: D003602:Cytotoxicity, Immunologic; D004357:Drug Synergism; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D004915:Leukemia, Erythroblastic, Acute / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008545:Melanoma / Q000276:immunology; D009369:Neoplasms / Q000276:immunology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma