Abstract

Ectopic lymphoid-like structures (ELSs) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicated poor prognosis for hepatocellular carcinoma (HCC). We studied an HCC mouse model that displayed abundant ELSs and found that they constituted immunopathological microniches wherein malignant hepatocyte progenitor cells appeared and thrived in a complex cellular and cytokine milieu until gaining self-sufficiency. The egress of progenitor cells and tumor formation were associated with the autocrine production of cytokines previously provided by the niche. ELSs developed via cooperation between the innate immune system and adaptive immune system, an event facilitated by activation of the transcription factor NF-κB and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy.

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Acknowledgements

We thank K. Kohno (Nara Institute of Science and Technology) for plasmids pBstN and p2335A-1; M.-A. Buendia (Institut Pasteur, France) for Myc-Trp53−/− liver tumors; V. Factor and S. Thorgeirsson (US National Institutes of Health) for anti-A6; and E. Cinnamon, M.-A. Buendia, K. Kohno, M. Ringelhan, R. Hillermann, D. Kull, I. Gat-Viks, Y. Steuerman, S. Itzkovitz and K. Bahar-Halpern for help and advice. Supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (E.P. and Y.B.-N.), the European Research Council (LIVERMICROENV to E.P.; PICHO to Y.B.-N.; and LiverCancerMechanism to M.H.), the Israel Science Foundation (E.P., Y.B.-N., I.S. and O.P.), the Israel Cancer Research Fund (Y.B.-N.), the Helmholtz alliance “preclinical comprehensive cancer center” Graduiertenkolleg (GRK482 to M.H.), Krebsliga Schweiz (Oncosuisse) (A.W.), Promedica Stiftung (A.W.), the US National Institutes of Health (CA118165, SRP ES010337 and AI0043477 to M.K.; and DK099558 to Y.H.), the Hildyard chair for Mitochondrial and Metabolic Diseases (M.K.), the Japan Society for the Promotion of Science (K.T.), Irma T Hirschl Trust (Y.H.), the FLAGS foundation (N.G.) and the Uehara Memorial Foundation (S.N.).

Author information

Affiliations

  1. Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

    • Shlomi Finkin
    • , Ilan Stein
    • , Michael Berger
    • , Yinon Ben-Neriah
    •  & Eli Pikarsky
  2. Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

    • Shlomi Finkin
    • , Ilan Stein
    • , Orit Pappo
    •  & Eli Pikarsky
  3. Institute of Virology, Technische Universität München, Helmholtz Zentrum München, Munich, Germany.

    • Detian Yuan
    •  & Mathias Heikenwalder
  4. Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA.

    • Koji Taniguchi
    •  & Michael Karin
  5. Institute of Surgical Pathology, University and University-Hospital Zurich, Zurich, Switzerland.

    • Achim Weber
  6. Research Unit of Radiation Cytogenetics, Helmholtz-Zentrum München, Ingolstädter-Landstrasse, Neuherberg, Germany.

    • Kristian Unger
  7. Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Jeffrey L Browning
  8. Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA.

    • Nicolas Goossens
    • , Shigeki Nakagawa
    •  & Yujin Hoshida
  9. Division of Gastroenterology & Hepatology Geneva University Hospital, Geneva, Switzerland.

    • Nicolas Goossens
  10. Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Ganesh Gunasekaran
    •  & Myron E Schwartz
  11. Department of Hepatology, Toranomon Hospital, Tokyo, Japan.

    • Masahiro Kobayashi
    •  & Hiromitsu Kumada
  12. Max Delbrück Center for Molecular Medicine, Berlin, Germany.

    • Klaus Rajewsky
  13. Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany.

    • Mathias Heikenwalder

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Contributions

K.R., M.Ka., M.H., Y.B.-N. and E.P. conceived of the study; S.F., D.Y. and I.S. designed and carried out most experiments and data analysis; K.T., A.W., K.U., N.G., S.N., G.G., M.E.S., M.Ko., H.K., M.B. and O.P. carried out additional experiments, contributed samples and performed data analysis; J.L.B. and K.R. supplied reagents; and S.F., D.Y., I.S., Y.H., M.Ka., M.H., Y.B.-N. and E.P. wrote the manuscript.

Competing interests

The authors have filed a provisional patent related to this manuscript.

Corresponding authors

Correspondence to Mathias Heikenwalder or Yinon Ben-Neriah or Eli Pikarsky.

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    Supplementary Figures 1–8 and Supplementary Tables 1–7

Videos

  1. 1.

    Progenitor cells egressing out of an ELS

    3D reconstruction of an ELS from DEN-treated IKKβ(EE)Hep mouse. Note green CD44v6+ progenitor cells egressing out of the ELS at multiple points.

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https://doi.org/10.1038/ni.3290

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