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

Eduardo J. Villablanca; Laura Raccosta; Dan Zhou; Raffaella Fontana; Daniela Maggioni; Aurora Negro; Francesca Sanvito; Maurilio Ponzoni; Barbara Valentinis; Marco Bregni; Alessandro Prinetti; Knut R. Steffensen; Sandro Sonnino; Jan Ake Gustafsson; Claudio Doglioni; Claudio Bordignon; Catia Traversari; Vincenzo Russo

doi:10.1038/nm.2074

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

Eduardo J. Villablanca, Laura Raccosta, Dan Zhou, Raffaella Fontana, Daniela Maggioni, Aurora Negro, Francesca Sanvito, Maurilio Ponzoni, Barbara Valentinis, Marco Bregni, Alessandro Prinetti, Knut R. Steffensen, Sandro Sonnino, Jan Ake Gustafsson, Claudio Doglioni, Claudio Bordignon, Catia Traversari, Vincenzo Russo

Houston Methodist

Research output: Contribution to journal › Article › peer-review

280 Scopus citations

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-α (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.

Original language	English (US)
Pages (from-to)	98-105
Number of pages	8
Journal	Nature Medicine
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/nm.2074
State	Published - Jan 2010

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm.2074

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Villablanca, E. J., Raccosta, L., Zhou, D., Fontana, R., Maggioni, D., Negro, A., Sanvito, F., Ponzoni, M., Valentinis, B., Bregni, M., Prinetti, A., Steffensen, K. R., Sonnino, S., Gustafsson, J. A., Doglioni, C., Bordignon, C., Traversari, C., & Russo, V. (2010). Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Nature Medicine, 16(1), 98-105. https://doi.org/10.1038/nm.2074

Villablanca, EJ, Raccosta, L, Zhou, D, Fontana, R, Maggioni, D, Negro, A, Sanvito, F, Ponzoni, M, Valentinis, B, Bregni, M, Prinetti, A, Steffensen, KR, Sonnino, S, Gustafsson, JA, Doglioni, C, Bordignon, C, Traversari, C & Russo, V 2010, 'Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses', Nature Medicine, vol. 16, no. 1, pp. 98-105. https://doi.org/10.1038/nm.2074

@article{63bc5223296144ffb625ec2e005747cb,

title = "Tumor-mediated liver X receptor-α 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-α (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.",

author = "Villablanca, {Eduardo J.} and Laura Raccosta and Dan Zhou and Raffaella Fontana and Daniela Maggioni and Aurora Negro and Francesca Sanvito and Maurilio Ponzoni and Barbara Valentinis and Marco Bregni and Alessandro Prinetti and Steffensen, {Knut R.} and Sandro Sonnino and Gustafsson, {Jan Ake} and Claudio Doglioni and Claudio Bordignon and Catia Traversari and Vincenzo Russo",

note = "Funding Information: We thank M.E. Bianchi and G. Parmiani for helpful discussions and for the critical review of this manuscript. Additionally, we thank D. Mangelsdorf, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, for providing us with GAL4LXRs plasmids; M. Lid{\'e}n, Ludwig Institute for Cancer Research, Stockholm, for GAL4RXR and TKMHC100luc plasmids; F. Nystrom, Link{\"o}ping University, for GAL4–PPARγ plasmid; C. Strott, National Institutes of Health, for the mouse SULT2B1b–encoding plasmid; L. Naldini, Scientific Institute S.Raffaele, for the lentiviral vector hPGK.GFP.wPRE.mhCMV.∆NGFr.SV40PA; and M. Rocchi and C. Lanterna for technical help. This work was supported by Fondazione Cariplo, Italian Association for Cancer Research, European Community Project {\textquoteleft}Cancer Immunotherapy{\textquoteright} LSHCCT2006518334 and the Italian Ministry of Health.",

year = "2010",

month = jan,

doi = "10.1038/nm.2074",

language = "English (US)",

volume = "16",

pages = "98--105",

journal = "Nature Medicine",

issn = "1078-8956",

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number = "1",

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T1 - Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses

AU - Villablanca, Eduardo J.

AU - Raccosta, Laura

AU - Zhou, Dan

AU - Fontana, Raffaella

AU - Maggioni, Daniela

AU - Negro, Aurora

AU - Sanvito, Francesca

AU - Ponzoni, Maurilio

AU - Valentinis, Barbara

AU - Bregni, Marco

AU - Prinetti, Alessandro

AU - Steffensen, Knut R.

AU - Sonnino, Sandro

AU - Gustafsson, Jan Ake

AU - Doglioni, Claudio

AU - Bordignon, Claudio

AU - Traversari, Catia

AU - Russo, Vincenzo

N1 - Funding Information: We thank M.E. Bianchi and G. Parmiani for helpful discussions and for the critical review of this manuscript. Additionally, we thank D. Mangelsdorf, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, for providing us with GAL4LXRs plasmids; M. Lidén, Ludwig Institute for Cancer Research, Stockholm, for GAL4RXR and TKMHC100luc plasmids; F. Nystrom, Linköping University, for GAL4–PPARγ plasmid; C. Strott, National Institutes of Health, for the mouse SULT2B1b–encoding plasmid; L. Naldini, Scientific Institute S.Raffaele, for the lentiviral vector hPGK.GFP.wPRE.mhCMV.∆NGFr.SV40PA; and M. Rocchi and C. Lanterna for technical help. This work was supported by Fondazione Cariplo, Italian Association for Cancer Research, European Community Project ‘Cancer Immunotherapy’ LSHCCT2006518334 and the Italian Ministry of Health.

PY - 2010/1

Y1 - 2010/1

N2 - 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-α (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.

AB - 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-α (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.

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

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