title: Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses.
abstract: Sterol metabolism has recently been linked to innate and adaptive immune responses through liver X receptor (LXR) signaling. Whether products of sterol metabolism interfere with antitumor responses is currently unknown. Dendritic cells (DCs) initiate immune responses, including antitumor activity after their CC chemokine receptor-7 (CCR7)-dependent migration to lymphoid organs. Here we report that human and mouse tumors produce LXR ligands that inhibit CCR7 expression on maturing DCs and, therefore, their migration to lymphoid organs. In agreement with this observation, we detected CD83(+)CCR7(-) DCs within human tumors. Mice injected with tumors expressing the LXR ligand-inactivating enzyme sulfotransferase 2B1b (SULT2B1b) successfully controlled tumor growth by regaining DC migration to tumor-draining lymph nodes and by developing overt inflammation within tumors. The control of tumor growth was also observed in chimeric mice transplanted with bone marrow from mice lacking the gene encoding LXR-alpha (Nr1h3(-/-) mice) Thus, we show a new mechanism of tumor immunoescape involving products of cholesterol metabolism. The manipulation of this pathway could restore antitumor immunity in individuals with cancer.
authors.affiliation: Cancer Gene Therapy Unit, Program of Immunology and Bio Immuno Gene Therapy of Cancer, Division of Molecular Oncology, Scientific Institute San Raffaele, Milan, Italy.
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Villablanca
authors.forename: Laura
authors.initials: L
authors.lastname: Raccosta
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: Raffaella
authors.initials: R
authors.lastname: Fontana
authors.forename: Daniela
authors.initials: D
authors.lastname: Maggioni
authors.forename: Aurora
authors.initials: A
authors.lastname: Negro
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Barbara
authors.initials: B
authors.lastname: Valentinis
authors.forename: Marco
authors.initials: M
authors.lastname: Bregni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prinetti
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.forename: Sandro
authors.initials: S
authors.lastname: Sonnino
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafsson
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Claudio
authors.initials: C
authors.lastname: Bordignon
authors.forename: Catia
authors.initials: C
authors.lastname: Traversari
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Russo
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D003713:Dendritic Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology; D000071518:Liver X Receptors; D008198:Lymph Nodes / Q000276:immunology / Q000503:physiopathology; D008545:Melanoma / Q000276:immunology / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D009374:Neoplasms, Experimental / Q000276:immunology / Q000503:physiopathology*; D057093:Orphan Nuclear Receptors / Q000502:physiology*; D054400:Receptors, CCR7 / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology; D019139:Tumor Escape / Q000276:immunology / Q000502:physiology*; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D007136:Immunoglobulins; D000071518:Liver X Receptors; D008562:Membrane Glycoproteins; D057093:Orphan Nuclear Receptors; D054400:Receptors, CCR7; D000097802:CD83 Antigen; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse