Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses.
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.
Villablanca
Eduardo J
EJ
Cancer Gene Therapy Unit, Program of Immunology and Bio Immuno Gene Therapy of Cancer, Division of Molecular Oncology, Scientific Institute San Raffaele, Milan, Italy.
Raccosta
Laura
L
Zhou
Dan
D
Fontana
Raffaella
R
Maggioni
Daniela
D
Negro
Aurora
A
Sanvito
Francesca
F
Ponzoni
Maurilio
M
Valentinis
Barbara
B
Bregni
Marco
M
Prinetti
Alessandro
A
Steffensen
Knut R
KR
Sonnino
Sandro
S
Gustafsson
Jan-Ake
JA
Doglioni
Claudio
C
Bordignon
Claudio
C
Traversari
Catia
C
Russo
Vincenzo
V
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
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