Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma

Shlomi Finkin, Detian Yuan, Ilan Stein, Koji Taniguchi, Achim Weber, Kristian Unger, Jeffrey L. Browning, Nicolas Goossens, Shigeki Nakagawa, Ganesh Gunasekaran, Myron E. Schwartz, Masahiro Kobayashi, Hiromitsu Kumada, Michael Berger, Orit Pappo, Klaus Rajewsky, Yujin Hoshida, Michael Karin, Mathias Heikenwalder, Yinon Ben-NeriahEli Pikarsky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

260 Scopus citations

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-? B and abolished by depletion of T cells. Such aberrant immunological foci might represent new targets for cancer therapy.

Original languageAmerican English
Pages (from-to)1235-1244
Number of pages10
JournalNature Immunology
Volume16
Issue number12
DOIs
StatePublished - 1 Dec 2015

Bibliographical note

Funding Information:
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.).

Publisher Copyright:
© 2015 Nature America, Inc.

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