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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.

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Figure 1: Tumors produce factors inhibiting CCR7 on DCs.
Figure 2: Tumor-conditioned media trigger LXR-α activation in DCs.
Figure 3: Blocking of LXR-α signaling abrogates CCR7 inhibition.
Figure 4: Dampening of DC migration and T cell priming by tumor-derived and synthetic LXR ligands and generation of antitumor responses by avoiding LXR-α signaling.
Figure 5: Dissection of the role of DCs, CCR7 and LXR-α in antitumor responses and characterization of infiltrating cells.

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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.

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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.

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Correspondence to Catia Traversari or Vincenzo Russo.

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

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Supplementary Figures 1–8, Supplementary Table 1 and Supplementary Methods (PDF 1551 kb)

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Villablanca, E., Raccosta, L., Zhou, D. et al. Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Nat Med 16, 98–105 (2010). https://doi.org/10.1038/nm.2074

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