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

Nature Medicine volume 16, pages 98105 (2010) | Download Citation

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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.

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Acknowledgements

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 GAL4-LXRs plasmids; M. Lidén, Ludwig Institute for Cancer Research, Stockholm, for GAL4-RXR and TK-MHC100-luc plasmids; F. Nystrom, Linköping University, for GAL4–PPAR-γ 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.ΔNGFr.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' LSHC-CT-2006-518334 and the Italian Ministry of Health.

Author information

Author notes

    • Catia Traversari
    •  & Vincenzo Russo

    These authors contributed equally to this work.

Affiliations

  1. Cancer Gene Therapy Unit, Program of Immunology and Bio Immuno Gene Therapy of Cancer, Division of Molecular Oncology, Scientific Institute San Raffaele, Milan, Italy.

    • Eduardo J Villablanca
    • , Laura Raccosta
    • , Raffaella Fontana
    • , Daniela Maggioni
    • , Aurora Negro
    • , Claudio Bordignon
    •  & Vincenzo Russo
  2. Università Vita-Salute San Raffaele, Milan, Italy.

    • Eduardo J Villablanca
    •  & Claudio Bordignon
  3. MolMed S.p.A., Milan, Italy.

    • Dan Zhou
    • , Barbara Valentinis
    • , Claudio Bordignon
    •  & Catia Traversari
  4. Department of Pathology, Scientific Institute San Raffaele, Milan, Italy.

    • Francesca Sanvito
    • , Maurilio Ponzoni
    •  & Claudio Doglioni
  5. Strategic Program of Oncology, Scientific Institute San Raffaele, Milan, Italy.

    • Marco Bregni
  6. Department of Medical Chemistry, Biochemistry and Biotechnology, Center of Excellence on Neurodegenerative Diseases, University of Milan, Segrate, Italy.

    • Alessandro Prinetti
    •  & Sandro Sonnino
  7. Department of Biosciences and Nutrition, Karolinska Institute, Novum, Huddinge, Sweden.

    • Knut R Steffensen
    •  & Jan-Ake Gustafsson
  8. Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas, USA.

    • Jan-Ake Gustafsson

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Contributions

E.J.V., L.R., D.Z., R.F., D.M., A.N., B.V., A.P. and V.R. performed in vitro and in vivo experiments. F.S., M.P. and C.D. analyzed and interpreted the immunohistochemistry and histology experiments. K.R.S. and J.-A.G. provided knockout mice and gave scientific advice. S.S., M.B. and C.B. provided a key contribution for the development of the project by discussing some aspects of the experimental strategies. E.J.V., C.T. and V.R. prepared the figures and drafted the manuscript. C.T. and V.R. contributed equally to the design of the experiments and to the writing of the manuscript.

Competing interests

J.-A.G. is a shareholder and consultant for KaroBio AB.

Corresponding authors

Correspondence to Catia Traversari or Vincenzo Russo.

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    Supplementary Text and Figures

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DOI

https://doi.org/10.1038/nm.2074