title: Inflammatory cytokine-mediated evasion of virus-induced tumors from NK cell control.
abstract: Infections with DNA tumor viruses, including members of the polyomavirus family, often result in tumor formation in immune-deficient hosts. The complex control involved in antiviral and antitumor immune responses during these infections can be studied in murine polyomavirus (PyV)-infected mice as a model. We found that NK cells efficiently kill cells derived from PyV-induced salivary gland tumors in vitro in an NKG2D (effector cell)-RAE-1 (target cell)-dependent manner; but in T cell-deficient mice, NK cells only delay but do not prevent the development of PyV-induced tumors. In this article, we show that the PyV-induced tumors have infiltrating functional NK cells. The freshly removed tumors, however, lack surface RAE-1 expression, and the tumor tissues produce soluble factors that downregulate RAE-1. These factors include the proinflammatory cytokines IL-1α, IL-1β, IL-33, and TNF. Each of these cytokines downregulates RAE-1 expression and susceptibility to NK cell-mediated cytotoxicity. CD11b(+)F4/80(+) macrophages infiltrating the PyV-induced tumors produce high amounts of IL-1β and TNF. Thus, our data suggest a new mechanism whereby inflammatory cytokines generated in the tumor environment lead to evasion of NK cell-mediated control of virus-induced tumors.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Rabinarayan
authors.initials: R
authors.lastname: Mishra
authors.forename: Bojan
authors.initials: B
authors.lastname: Polic
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Welsh
authors.forename: Eva
authors.initials: E
authors.lastname: Szomolanyi-Tsuda
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D011120:Polyomavirus / Q000276:immunology*; D027601:Polyomavirus Infections / Q000276:immunology; D012468:Salivary Gland Neoplasms / Q000276:immunology* / Q000821:virology; D019139:Tumor Escape; D059016:Tumor Microenvironment / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000378:metabolism; D014412:Tumor Virus Infections / Q000276:immunology
chemical_list: D039481:CD11b Antigen; C506535:Il33 protein, mouse; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D000067596:Interleukin-33; D007378:Interleukins; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; C490521:Rae1 protein, mouse; D048069:Tumor Necrosis Factors