title: p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells.
abstract: The induction of cellular senescence is an important mechanism by which p53 suppresses tumorigenesis. Using a mouse model of liver carcinoma, where cellular senescence is triggered in vivo by inducible p53 expression, we demonstrated that NK cells participate in the elimination of senescent tumors. The elimination of senescent tumor cells is dependent on NKG2D. Interestingly, p53 restoration neither increases ligand expression nor increases the sensitivity to lysis by NK cells. Instead, p53 restoration caused tumor cells to secrete various chemokines with the potential to recruit NK cells. Antibody-mediated neutralization of CCL2, but not CCL3, CCL4 or CCL5, prevented NK cell recruitment to the senescent tumors and reduced their elimination. Our findings suggest that elimination of senescent tumors by NK cells occurs as a result of the cooperation of signals associated with p53 expression or senescence, which regulate NK cell recruitment, and other signals that induce NKG2D ligand expression on tumor cells.
authors.affiliation: Berkeley, Berkeley, CA 94720.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Iannello
authors.forename: Thornton W
authors.initials: TW
authors.lastname: Thompson
authors.forename: Michele
authors.initials: M
authors.lastname: Ardolino
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.forename: David H
authors.initials: DH
authors.lastname: Raulet
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis*; D003602:Cytotoxicity, Immunologic; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D018932:Chemokine CCL2; D018925:Chemokines; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016159:Tumor Suppressor Protein p53
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