title: NKG2D function protects the host from tumor initiation.
abstract: The activation NKG2D receptor has been shown to play an important role in the control of experimental tumor growth and metastases expressing ligands for NKG2D; however, a function for this recognition pathway in host protection from de novo tumorigenesis has never been demonstrated. We show that neutralization of NKG2D enhances the sensitivity of wild-type (WT) C57BL/6 and BALB/c mice to methylcholanthrene (MCA)-induced fibrosarcoma. The importance of the NKG2D pathway was additionally illustrated in mice deficient for either IFN-gamma or tumor necrosis factor-related apoptosis-inducing ligand, whereas mice depleted of natural killer cells, T cells, or deficient for perforin did not display any detectable NKG2D phenotype. Furthermore, IL-12 therapy preventing MCA-induced sarcoma formation was also largely dependent on the NKG2D pathway. Although NKG2D ligand expression was variable or absent on sarcomas emerging in WT mice, sarcomas derived from perforin-deficient mice were Rae-1(+) and immunogenic when transferred into WT syngeneic mice. These findings suggest an important early role for the NKG2D in controlling and shaping tumor formation.
authors.affiliation: Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. mark.smyth@petermac.org
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Jeremy
authors.initials: J
authors.lastname: Swann
authors.forename: Erika
authors.initials: E
authors.lastname: Cretney
authors.forename: Nadeen
authors.initials: N
authors.lastname: Zerafa
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency; D002352:Carrier Proteins / Q000378:metabolism; D005354:Fibrosarcoma / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency; D008565:Membrane Proteins; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009500:Neutralization Tests; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; C527086:Klrk1 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D052899:Pore Forming Cytotoxic Proteins; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C468260:UL16 binding protein 1, mouse; D054353:Perforin; D018664:Interleukin-12; D008748:Methylcholanthrene