Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features
Open accessAbstract
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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Inflamed tumours make up about 30% of hepatocellular carcinomas and show extensive immune infiltration, increased immune checkpoint expression, interferon signalling activation, and a low burden of large chromosomal alterations.
“Inflamed tumours constitute ~30% of HCCs and exhibit extensive immune cell infiltration and immune activity, detected as increased expression of immune checkpoints (such as PD-1 or its ligand PD-L1), activation of IFN signalling and a low burden of large chromosomal alterations70,71,78.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [71]
High tumour mutational burden does not correlate with increased immune infiltration in hepatocellular carcinoma.
“Furthermore, a high TMB does not correlate with increased immune infiltration70,71.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [71]
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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
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 153
- Issue
- 3
- Pages
- 812-826
- ISSN
- 0016-5085 (ISSN-L)
- 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
- 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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