Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses

被引:260
作者
Villablanca, Eduardo J. [1 ,2 ]
Raccosta, Laura [1 ]
Zhou, Dan [3 ]
Fontana, Raffaella [1 ]
Maggioni, Daniela [1 ]
Negro, Aurora [1 ]
Sanvito, Francesca [4 ]
Ponzoni, Maurilio [4 ]
Valentinis, Barbara [3 ]
Bregni, Marco [5 ]
Prinetti, Alessandro [6 ]
Steffensen, Knut R. [7 ]
Sonnino, Sandro [6 ]
Gustafsson, Jan-Ake [7 ,8 ]
Doglioni, Claudio [4 ]
Bordignon, Claudio [1 ,3 ]
Traversari, Catia [3 ]
Russo, Vincenzo [1 ]
机构
[1] Ist Sci San Raffaele, Div Mol Oncol, Program Immunol & Bio Immuno Gene Therapy Canc, Canc Gene Therapy Unit, I-20132 Milan, Italy
[2] Univ Vita Salute San Raffaele, Milan, Italy
[3] MolMed SpA, Milan, Italy
[4] Ist Sci San Raffaele, Dept Pathol, I-20132 Milan, Italy
[5] Ist Sci San Raffaele, Strateg Program Oncol, I-20132 Milan, Italy
[6] Univ Milan, Dept Med Chem Biochem & Biotechnol, Ctr Excellence Neurodegenerat Dis, Segrate, Italy
[7] Karolinska Inst, Novum, Dept Biosci & Nutr, Huddinge, Sweden
[8] Univ Houston, Ctr Nucl Receptors & Cell Signaling, Houston, TX USA
关键词
NUCLEAR RECEPTORS; T-CELLS; MIGRATION; METABOLISM; CHOLESTEROL; IMMUNOGENICITY; INFLAMMATION; OXYSTEROLS; DEPLETION; THERAPY;
D O I
10.1038/nm.2074
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:98 / U137
页数:9
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