Classification of primary liver cancer with immunosuppression mechanisms and correlation with genomic alterations.

Aged Cell Line, Tumor Chemokines / genetics Female Humans Liver / metabolism Liver Neoplasms / classification Male Middle Aged Transcription Factors / genetics Transcriptome Tumor Escape / genetics Tumor Microenvironment
Liver cancer Regulatory T cell Tumor microenvironment Tumor-associated macrophage

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
Mar 2020
Historique:
received: 30 09 2019
revised: 21 01 2020
accepted: 22 01 2020
pubmed: 1 3 2020
medline: 18 12 2020
entrez: 1 3 2020
Statut: ppublish

Résumé

The tumor microenvironment can be classified into immunologically active "inflamed" tumors and inactive "non-inflamed" tumors based on the infiltration of cytotoxic immune cells. Previous studies on liver cancer have reported a superior prognosis for inflamed tumors compared to non-inflamed tumors. However, liver cancer is highly heterogeneous immunologically and genetically, and a finer classification of the liver cancer microenvironment may improve our understanding of its immunological diversity and response to immune therapy. We characterized the immune gene signatures of 234 primary liver cancers, mainly virus-related, from a Japanese population using RNA-Seq of tumors and matched non-tumorous hepatitis livers. We then compared them with the somatic alterations detected using the whole-genome sequencing. Liver cancers expressed lower levels of immune marker genes than non-tumorous hepatitis livers, indicating immunosuppression in the tumor microenvironment. Several immunosuppression mechanisms functioned actively and mutually exclusively, resulting in four immune subclasses of liver cancer: tumor-associated macrophage (TAM), CTNNB1, cytolytic activity (CYT), and regulatory T cell (Treg). The CYT and Treg subclasses represented inflamed tumors, while the TAM and CTNNB1 subclasses represented non-inflamed tumors. The TAM subclass, which comprised 31% of liver cancers, showed a poor survival, expressed elevated levels of extracellular matrix genes, and was associated with somatic mutations of chromatin regulator ARID2. The results of cell line experiments suggested a functional link between ARID2 and chemokine production by liver cancer cells. Primary liver cancer was classified into four subclasses based on mutually exclusive mechanisms for immunosuppression. This classification indicate the importance of immunosuppression mechanisms, such as TAM and Treg, as therapeutic targets for liver cancer. The Japan Agency for Medical Research and Development (AMED).

Sections du résumé

BACKGROUND BACKGROUND
The tumor microenvironment can be classified into immunologically active "inflamed" tumors and inactive "non-inflamed" tumors based on the infiltration of cytotoxic immune cells. Previous studies on liver cancer have reported a superior prognosis for inflamed tumors compared to non-inflamed tumors. However, liver cancer is highly heterogeneous immunologically and genetically, and a finer classification of the liver cancer microenvironment may improve our understanding of its immunological diversity and response to immune therapy.
METHODS METHODS
We characterized the immune gene signatures of 234 primary liver cancers, mainly virus-related, from a Japanese population using RNA-Seq of tumors and matched non-tumorous hepatitis livers. We then compared them with the somatic alterations detected using the whole-genome sequencing.
FINDINGS RESULTS
Liver cancers expressed lower levels of immune marker genes than non-tumorous hepatitis livers, indicating immunosuppression in the tumor microenvironment. Several immunosuppression mechanisms functioned actively and mutually exclusively, resulting in four immune subclasses of liver cancer: tumor-associated macrophage (TAM), CTNNB1, cytolytic activity (CYT), and regulatory T cell (Treg). The CYT and Treg subclasses represented inflamed tumors, while the TAM and CTNNB1 subclasses represented non-inflamed tumors. The TAM subclass, which comprised 31% of liver cancers, showed a poor survival, expressed elevated levels of extracellular matrix genes, and was associated with somatic mutations of chromatin regulator ARID2. The results of cell line experiments suggested a functional link between ARID2 and chemokine production by liver cancer cells.
INTERPRETATION CONCLUSIONS
Primary liver cancer was classified into four subclasses based on mutually exclusive mechanisms for immunosuppression. This classification indicate the importance of immunosuppression mechanisms, such as TAM and Treg, as therapeutic targets for liver cancer.
FUNDING BACKGROUND
The Japan Agency for Medical Research and Development (AMED).

Identifiants

DOI: 10.1016/j.ebiom.2020.102659 PMID: 32113157 PMC: PMC7048625
pubmed: 32113157
pii: S2352-3964(20)30034-7
doi: 10.1016/j.ebiom.2020.102659
pmc: PMC7048625
pii:
doi:

Substances chimiques

ARID2 protein, human 0
Chemokines 0
Transcription Factors 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

102659

Informations de copyright

Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare no competing interests.

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Auteurs

Masashi Fujita (M)

Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Electronic address: m-fujita@riken.jp.

Rui Yamaguchi (R)

Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address: ruiy@ims.u-tokyo.ac.jp.

Takanori Hasegawa (T)

Health Intelligence Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address: t-hasegw@ims.u-tokyo.ac.jp.

Shu Shimada (S)

Department of Molecular Oncology Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: shimada.monc@tmd.ac.jp.

Koji Arihiro (K)

Department of Anatomical Pathology, Hiroshima University, Hiroshima, Japan. Electronic address: arihiro@hiroshima-u.ac.jp.

Shuto Hayashi (S)

Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address: s-haya@hgc.jp.

Kazuhiro Maejima (K)

Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Electronic address: kazuhiro.maejima@riken.jp.

Kaoru Nakano (K)

Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Electronic address: kaoru.nakano@riken.jp.

Akihiro Fujimoto (A)

Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: afujimoto@m.u-tokyo.ac.jp.

Atsushi Ono (A)

Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address: atsushi-o@hiroshima-u.ac.jp.

Hiroshi Aikata (H)

Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address: aikata@hiroshima-u.ac.jp.

Masaki Ueno (M)

Second Department of Surgery, Wakayama Medical University, Wakayama, Japan. Electronic address: ma@wakayama-med.ac.jp.

Shinya Hayami (S)

Second Department of Surgery, Wakayama Medical University, Wakayama, Japan. Electronic address: shin-8@wakayama-med.ac.jp.

Hiroko Tanaka (H)

Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address: hiroko@hgc.jp.

Satoru Miyano (S)

Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Health Intelligence Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address: miyano@ims.u-tokyo.ac.jp.

Hiroki Yamaue (H)

Second Department of Surgery, Wakayama Medical University, Wakayama, Japan. Electronic address: yamaue-h@wakayama-med.ac.jp.

Kazuaki Chayama (K)

Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address: chayama@hiroshima-u.ac.jp.

Kazuhiro Kakimi (K)

Department of Immuno-therapeutics, The University of Tokyo Hospital, Japan; Cancer Immunology Data Multi-level Integration Unit, RIKEN Medical Innovation Hub Program, Tokyo, Japan. Electronic address: kakimi@m.u-tokyo.ac.jp.

Shinji Tanaka (S)

Department of Molecular Oncology Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: tanaka.monc@tmd.ac.jp.

Seiya Imoto (S)

Health Intelligence Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Electronic address: imoto@ims.u-tokyo.ac.jp.

Hidewaki Nakagawa (H)

Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Electronic address: hidewaki@riken.jp.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Classification of primary liver cancer with...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Classification of primary liver cancer with...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Chimiokines › Classification of primary liver cancer with...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Classification of primary liver cancer with...
questionsmedicales.fr › Système digestif › Foie › Classification of primary liver cancer with...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Classification of primary liver cancer with...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Classification of primary liver cancer with...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Classification of primary liver cancer with...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Transcriptome › Classification of primary liver cancer with...
questionsmedicales.fr › Phénomènes du système immunitaire › Échappement de la tumeur à la surveillance immunitaire › Classification of primary liver cancer with...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › Classification of primary liver cancer with...