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

Research output: Contribution to journalArticle

139 Citations (Scopus)

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 languageEnglish
Pages (from-to)98-105
Number of pages8
JournalNature Medicine
Volume16
Issue number1
DOIs
Publication statusPublished - Jan 2010

Fingerprint

CCR7 Receptors
Liver
Dendritic Cells
Tumors
Chemical activation
Neoplasms
Metabolism
Sterols
Ligands
Sulfotransferases
Gene encoding
Liver X Receptors
Adaptive Immunity
Growth
Innate Immunity
Bone
Cell Movement
Immunity
Cholesterol
Lymph Nodes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. / Villablanca, Eduardo J.; Raccosta, Laura; Zhou, Dan; Fontana, Raffaella; Maggioni, Daniela; Negro, Aurora; Sanvito, Francesca; Ponzoni, Maurilio; Valentinis, Barbara; Bregni, Marco; Prinetti, Alessandro; Steffensen, Knut R.; Sonnino, Sandro; Gustafsson, Jan Ake; Doglioni, Claudio; Bordignon, Claudio; Traversari, Catia; Russo, Vincenzo.

In: Nature Medicine, Vol. 16, No. 1, 01.2010, p. 98-105.

Research output: Contribution to journalArticle

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
Villablanca, Eduardo J. ; Raccosta, Laura ; Zhou, Dan ; Fontana, Raffaella ; Maggioni, Daniela ; Negro, Aurora ; Sanvito, Francesca ; Ponzoni, Maurilio ; Valentinis, Barbara ; Bregni, Marco ; Prinetti, Alessandro ; Steffensen, Knut R. ; Sonnino, Sandro ; Gustafsson, Jan Ake ; Doglioni, Claudio ; Bordignon, Claudio ; Traversari, Catia ; Russo, Vincenzo. / Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. In: Nature Medicine. 2010 ; Vol. 16, No. 1. pp. 98-105.
@article{ed7451284bbc4d528d702cec3c0f2d1d,
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",
year = "2010",
month = "1",
doi = "10.1038/nm.2074",
language = "English",
volume = "16",
pages = "98--105",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

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

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.

UR - http://www.scopus.com/inward/record.url?scp=73849096869&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73849096869&partnerID=8YFLogxK

U2 - 10.1038/nm.2074

DO - 10.1038/nm.2074

M3 - Article

VL - 16

SP - 98

EP - 105

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 1

ER -