title: Melanoma cells become resistant to NK-cell-mediated killing when exposed to NK-cell numbers compatible with NK-cell infiltration in the tumor.
abstract: During the past few years, a number of studies reported that different melanoma cell lines could be extensively lysed in vitro by IL-2-activated NK cells at appropriate effector/target ratios. Here, we show, by histological evaluation of different melanoma lesions, that NK/target-cell ratios compatible with those allowing efficient melanoma cell killing in vitro are hardly reached at the tumor site. We then investigated the outcome of cocultures established at low NK/melanoma cell ratios. After initial NK-mediated lysis, residual melanoma cells acquired resistance to IL-2-activated NK cells. This reflected primarily an increased expression, on melanoma cells, of classical and nonclassical HLA class I molecules, accompanied by a partial downregulation of NKG2D-ligands, and was dependent on NK-mediated IFN-γ release. Consistently, melanoma lesions showed a higher HLA class I expression on tumor cells that were proximal to infiltrating NK cells. In long-term cocultures, the "protective phenotype" acquired by melanoma cells was lost over time. However, this phenomenon was counteracted by downregulation of relevant activating receptors in cocultured NK cells. Analysis of different NK-cell-activating cytokines indicated that IL-15 can partially overcome this novel tumor escape mechanism suggesting that IL-15, rather than IL-2, may be eligible for NK-cell-based immunotherapy.
authors.affiliation: Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Mirna
authors.initials: M
authors.lastname: Balsamo
authors.forename: William
authors.initials: W
authors.lastname: Vermi
authors.forename: Monica
authors.initials: M
authors.lastname: Parodi
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pietra
authors.forename: Claudia
authors.initials: C
authors.lastname: Manzini
authors.forename: Paola
authors.initials: P
authors.lastname: Queirolo
authors.forename: Silvia
authors.initials: S
authors.lastname: Lonardi
authors.forename: Raffaella
authors.initials: R
authors.lastname: Augugliaro
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mingari
authors.forename: Massimo
authors.initials: M
authors.lastname: Vitale
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D019409:Interleukin-15; D007371:Interferon-gamma