title: NK-cell-dependent killing of colon carcinoma cells is mediated by natural cytotoxicity receptors (NCRs) and stimulated by parvovirus infection of target cells.
abstract: BACKGROUND
  Investigating how the immune system functions during malignancies is crucial to developing novel therapeutic strategies. Natural killer (NK) cells, an important component of the innate immune system, play a vital role in immune defense against tumors and virus-infected cells. The poor survival rate in colon cancer makes it particularly important to develop novel therapeutic strategies. Oncolytic viruses, in addition to lysing tumor cells, may have the potential to augment antitumor immune responses. In the present study, we investigate the role of NK cells and how parvovirus H-1PV can modulate NK-cell mediated immune responses against colon carcinoma.
  
  
  METHODS
  Human NK cells were isolated from the blood of healthy donors. The cytotoxicity and antibody-mediated inhibition of NK cells were measured in chromium release assays. Phenotypic assessment of colon cancer and dendritic cells was done by FACS. The statistical significance of the results was calculated with Student's t test (*p <0.05; **, p < 0.01; ***, p < 0.001).
  
  
  RESULTS
  We show that IL-2-activated human NK cells can effectively kill colon carcinoma cells. Killing of colon carcinoma cells by NK cells was further enhanced upon infection of the former cells with parvovirus H-1PV. H-1PV has potent oncolytic activity against various tumors, yet its direct killing effect on colon carcinoma cells is limited. The cytotoxicity of NK cells towards colon carcinoma cells, both mock- and H-1PV-infected, was found to be mostly mediated by a combination of natural cytotoxicity receptors (NCRs), namely NKp30, 44, and 46. Colon carcinoma cells displayed low to moderate expression of NK cell ligands, and this expression was modulated upon H-1PV infection. Lysates of H-1PV-infected colon carcinoma cells were found to increase MHC class II expression on dendritic cells.
  
  
  CONCLUSIONS
  Altogether, these data suggest that IL-2-activated NK cells actively kill colon carcinoma cells and that this killing is mediated by several natural cytotoxicity receptors (NCRs) in combination. Additionally, in association with parvovirus H-1PV, IL-2-activated NK cells have the potential to boost immune responses against colon cancer.
authors.affiliation: German Cancer Research Center (DKFZ), Tumor Virology, F010, Im Neuenheimer Feld 242, Heidelberg D-69120, Germany. r.bhat@dkfz.de
authors.forename: Rauf
authors.initials: R
authors.lastname: Bhat
authors.forename: Jean
authors.initials: J
authors.lastname: Rommelaere
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000821:virology; D003110:Colonic Neoplasms / Q000276:immunology* / Q000821:virology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D052661:H-1 parvovirus / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000276:immunology; D010322:Parvoviridae Infections / Q000276:immunology
chemical_list: D007376:Interleukin-2
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