title: Activation of immature hepatic NK cells as immunotherapy for liver metastatic disease.
abstract: NK cells can identify and eliminate emerging tumors due to altered expression of activating and inhibitory ligands on aberrant cells, a process that is greatly enhanced following NK cell activation. As a principal site of both tumor metastases and immature NK cells, the liver represents a unique anatomic location in which activation of the innate immune system could provide substantial therapeutic benefit. We describe here the NK cell-dependent destruction of a primary hepatic tumor following infection with an attenuated intracellular bacterium derived from Listeria monocytogenes. NK cell-mediated immunity correlated with the ordered migration and maturation of NK cells within the liver. Cytolytic activity was partially dependent on NKG2D-mediated tumor cell recognition, but surprisingly was still effective in the absence of type I IFN. Significantly, NK cell-mediated destruction of a primary hepatic tumor in infected mice led to long-lived CD4- and CD8 T cell-dependent tumor-specific adaptive immunity. These findings establish that activation and differentiation of immature NK cells using complex microbial stimuli can elicit potent anti-tumor activity within the liver, promote cross-presentation of tumor-derived Ags leading to long-lived systemic anti-tumor immunity, and suggests a paradigm for clinical intervention of liver metastatic carcinoma.
authors.affiliation: Cerus Corporation, Concord, CA 94520, USA. reprints@keithbahjat.com
authors.forename: Keith S
authors.initials: KS
authors.lastname: Bahjat
authors.forename: Rodney A
authors.initials: RA
authors.lastname: Prell
authors.forename: Heather E
authors.initials: HE
authors.lastname: Allen
authors.forename: Weiqun
authors.initials: W
authors.lastname: Liu
authors.forename: Edward E
authors.initials: EE
authors.lastname: Lemmens
authors.forename: Meredith L
authors.initials: ML
authors.lastname: Leong
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Portnoy
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Dubensky
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Brockstedt
authors.forename: Martin A
authors.initials: MA
authors.lastname: Giedlin
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D007111:Immunity, Cellular; D007113:Immunity, Innate; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology; D008113:Liver Neoplasms / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000276:immunology / Q000627:therapeutic use; D055607:Receptors, Natural Killer Cell
chemical_list: C527086:Klrk1 protein, mouse; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D007371:Interferon-gamma