title: Defective lymphokine production by most CD8+ and CD4+ tumor-specific T cell clones derived from human melanoma-infiltrating lymphocytes in response to autologous tumor cells in vitro.
abstract: Human melanomas are infiltrated by tumor-reactive T lymphocytes. However, the ability of these cells to elicit a specific anti-tumor response in vivo remains to be established. Because lymphokine production is critical for T cell functions, we have analyzed the capacity of melanoma-specific tumor-infiltrating lymphocyte (TIL) clones to produce major lymphokines: interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), as well as tumor necrosis factor (TNF), in response to direct antigen presentation by autologous and allogeneic tumor cells. We report here that, upon stimulation by autologous melanoma cells, all TIL clones secreted TNF but only a few of them produced significant amounts of IL-2, IL-4 or IFN-gamma. Nonetheless, all these clones consistently produced two or three of these last lymphokines upon stimulation with phorbol myristate acetate and calcium ionophore, as well as IL-2 upon CD3 stimulation, showing the existence of three lymphokine profiles among them: Th1, Th0 and a profile characterized by IL-2 and IL-4, but not IFN-gamma secretion. Stimulation of TIL clones by allogeneic melanoma lines sharing the appropriate HLA-peptide complexes revealed that defective IL-2 production seemed to be a constant feature for some clones, while it was, for other clones, dependent on the antigen-presenting tumor cells. For this last type of clone, we further showed that defective IL-2 induction resulted from an LFA-3 defect of some melanoma cells or from distinct yet undefined defects of other melanoma lines. Our data suggest that defective lymphokine secretion may be an essential component of the in vivo failure of melanoma-reactive TIL to control tumor development. Interestingly both CD4+ and CD8+ TIL clones from one patient were fully activated by the autologous melanoma cells in vitro, supporting a potential role of such TIL in spontaneous or induced tumor rejection.
authors.affiliation: Unité 211 INSERM; Faculté des Sciences de Nantes, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Guilloux
authors.forename: C
authors.initials: C
authors.lastname: Viret
authors.forename: N
authors.initials: N
authors.lastname: Gervois
authors.forename: E
authors.initials: E
authors.lastname: Le Dréan
authors.forename: M C
authors.initials: MC
authors.lastname: Pandolfino
authors.forename: E
authors.initials: E
authors.lastname: Diez
authors.forename: F
authors.initials: F
authors.lastname: Jotereau
mesh_terms: D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000502:physiology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018968:CD58 Antigens; D016827:CD8 Antigens / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D007476:Ionophores / Q000494:pharmacology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D017252:CD3 Complex; D018968:CD58 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D007376:Interleukin-2; D007476:Ionophores; D008562:Membrane Glycoproteins; D013755:Tetradecanoylphorbol Acetate