Cited by 1,000Cancer Immunotherapy and BiomarkersHepatocellular Carcinoma Treatment and PrognosisHepatitis B Virus Studies

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Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features

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Sia, Daniela, Jiao, Yang, Martinez-Quetglas, Iris, Kuchuk, Olga, Villacorta-Martin, Carlos, Castro de Moura, Manuel, Putra, Juan, Camprecios, Genis, Bassaganyas, Laia, Akers, Nicholas, Losic, Bojan, Waxman, Samuel, Thung, Swan N., Mazzaferro, Vincenzo, Esteller, Manel, Friedman, Scott L., Schwartz, Myron, Villanueva, Augusto, Llovet, Josep M.·2017·Gastroenterology

DOI 10.1053/j.gastro.2017.06.007PMC PMC12166766

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Abstract

Background & aims Agents that induce an immune response against tumors by altering T-cell regulation have increased survival times of patients with advanced-stage tumors, such as melanoma or lung cancer. We aimed to characterize molecular features of immune cells that infiltrate hepatocellular carcinomas (HCCs) to determine whether these types of agents might be effective against liver tumors.Methods We analyzed HCC samples from 956 patients. We separated gene expression profiles from tumor, stromal, and immune cells using a non-negative matrix factorization algorithm. We then analyzed the gene expression pattern of inflammatory cells in HCC tumor samples. We correlated expression patterns with the presence of immune cell infiltrates and immune regulatory molecules, determined by pathology and immunohistochemical analyses, in a training set of 228 HCC samples. We validated the correlation in a validation set of 728 tumor samples. Using data from 190 tumors in the Cancer Genome Atlas, we correlated immune cell gene expression profiles with numbers of chromosomal aberrations (based on single-nucleotide polymorphism array) and mutations (exome sequence data).Results We found approximately 25% of HCCs to have markers of an inflammatory response, with high expression levels of the CD274 molecule (programmed death-ligand 1) and programmed cell death 1, markers of cytolytic activity, and fewer chromosomal aberrations. We called this group of tumors the Immune class. It contained 2 subtypes, characterized by markers of an adaptive T-cell response or exhausted immune response. The exhausted immune response subclass expressed many genes regulated by transforming growth factor beta 1 that mediate immunosuppression. We did not observe any differences in numbers of mutations or expression of tumor antigens between the immune-specific class and other HCCs.Conclusions In an analysis of HCC samples from 956 patients, we found almost 25% to express markers of an inflammatory response. We identified 2 subclasses, characterized by adaptive or exhausted immune responses. These findings indicate that some HCCs might be susceptible to therapeutic agents designed to block the regulatory pathways in T cells, such as programmed death-ligand 1, programmed cell death 1, or transforming growth factor beta 1 inhibitors.

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Authors: Sia, D., Jiao, Y., Martinez-Quetglas, I., Kuchuk, O., Villacorta-Martin, C., Castro de Moura, M., Putra, J., Camprecios, G., Bassaganyas, L., Akers, N., Losic, B., Waxman, S., Thung, S. N., Mazzaferro, V., Esteller, M., Friedman, S. L., Schwartz, M., Villanueva, A., & Llovet, J. M.
Affiliations: Tisch Cancer Institute (US)
Hospital Clínic de Barcelona (ES)
University of Milan (IT)
Institució Catalana de Recerca i Estudis Avançats (ES)
Corresponding author: Llovet, Josep M.
ORCID: Sia, Daniela
Kuchuk, Olga
Villacorta-Martin, Carlos
Castro de Moura, Manuel
Putra, Juan
Bassaganyas, Laia
Akers, Nicholas
Losic, Bojan
Thung, Swan N.
Mazzaferro, Vincenzo
Esteller, Manel
Friedman, Scott L.
Villanueva, Augusto
Llovet, Josep M.
Venue: Gastroenterology
Publisher: Elsevier BV
Published: 2017-09
Volume: 153
Issue: 3
Pages: 812-826
ISSN: 0016-5085 (ISSN-L)
DOI: 10.1053/j.gastro.2017.06.007
PMC: PMC12166766
OpenAlex: W2626033245
Cited by: 976
References: 46
Citations by year: 2026: 65 · 2025: 82 · 2024: 124 · 2023: 136 · 2022: 155 · 2021: 188 · 2020: 104 · 2019: 72 · 2018: 41 · 2017: 9
FWCI: 27.37
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (am, 363 d)
Locations: Gastroenterology (acceptedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (acceptedVersion, cc-by-nc-nd)
Funders: Tisch Cancer Institute (P30 CA196521)
US Department of Defense (CA150272P3)
European Commission Framework Program 7 (259744)
Horizon 2020 Program (667273–2)
Asociación Española Contra el Cáncer
Samuel Waxman Cancer Research Foundation
Spanish National Health Institute (SAF2013–41027)
Grup de Recerca Consolidat–Recerca Translacional en Oncologia Hepàtica
AGAUR (SGR 1162)
European Commission HEPCAR
Onlus Prometeo
Hepato-Oncology Research Project
Istituto Nazionale Tumori
National Cancer Institute
IRCCS Foundation
Juan de la Cierva Fellowship
Associazione Italiana per la Ricerca sul Cancro
Italian Ministry of Health
National Institutes of Health (R01DK56621)
American Association
Liver Diseases Foundation Alan Hofmann Clinical and Translational Award
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
Keywords: hepatocellular carcinoma, tumor immune microenvironment, immune cell infiltration, PD-1, T cell exhaustion, TGF-β1, chromosomal abnormalities, cancer mutations, tumor-infiltrating immune cells, immune checkpoint inhibitors, tumor subtypes, gene expression profiling, non-negative matrix factorization, tides
MeSH terms: Aged, Female, Carcinoma, Hepatocellular, Humans, Immune Tolerance, Immunohistochemistry, Liver Neoplasms, Male, Middle Aged, Mutation, Signal Transduction, Gene Expression Regulation, Neoplastic, Immunophenotyping, Lymphocytes, Tumor-Infiltrating, DNA Methylation, beta Catenin, Transforming Growth Factor beta1, Adaptive Immunity, Tumor Microenvironment, Transcriptome, B7-H1 Antigen, Programmed Cell Death 1 Receptor

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Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features

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