title: Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma.
abstract: Evasion of host immune responses is well documented for viruses and may also occur during tumor immunosurveillance. The mechanisms involve alterations in MHC class I expression, Ag processing and presentation, chemokine and cytokine production, and lymphocyte receptor expression. Epithelial tumors overexpress MHC class I chain-related (MIC) molecules, which are ligands for the activating receptor NKG2D on NK and T cells. We report that NK cells from patients with colorectal cancer lack expression of activating NKG2D and chemokine CXCR1 receptors, both of which are internalized. Serum levels of soluble MIC (sMIC) are elevated and are responsible for down-modulation of NKG2D and CXCR1. In contrast, high serum levels of CXC ligands, IL-8, and epithelial-neutrophil-activating peptide (ENA-78) do not down-modulate CXCR1. In vitro, internalization of NKG2D and CXCR1 occurs within 4 and 24 h, respectively, of incubating normal NK cells with sMIC-containing serum. Furthermore, natural cytotoxicity receptor NKp44 and chemokine receptor CCR7 are also down-modulated in IL-2-activated NK cells cocultured in MIC-containing serum-an effect secondary to the down-modulation of NKG2D and not directly caused by physical association with sMIC. The patients' NK cells up-regulate expression of NKG2D, NKp44, CXCR1, and CCR7 when cultured in normal serum or anti-MIC Ab-treated autologous serum. NKG2D(+) but not NKG2D(-) NK cells are tumoricidal in vitro, and in vivo they selectively traffic to the xenografted carcinoma, form immunological synapse with tumor cells, and significantly retard tumor growth in the SCID mice. These results suggest that circulating sMIC in the cancer patients deactivates NK immunity by down-modulating important activating and chemokine receptors.
authors.affiliation: Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Doubrovina
authors.forename: Mikhail M
authors.initials: MM
authors.lastname: Doubrovin
authors.forename: Elena
authors.initials: E
authors.lastname: Vider
authors.forename: Richard B
authors.initials: RB
authors.lastname: Sisson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: O'Reilly
authors.forename: Bo
authors.initials: B
authors.lastname: Dupont
authors.forename: Yatin M
authors.initials: YM
authors.lastname: Vyas
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002461:Cell Line, Transformed; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007111:Immunity, Cellular; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D008024:Ligands; D051379:Mice; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D009368:Neoplasm Transplantation; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D055607:Receptors, Natural Killer Cell; D012995:Solubility; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000276:immunology*
chemical_list: C515370:CCR7 protein, human; C515371:Ccr7 protein, mouse; D006131:Growth Inhibitors; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D011971:Receptors, Immunologic; D023062:Receptors, Interleukin-8A; D055607:Receptors, Natural Killer Cell