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

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

Research output: Contribution to journalArticle

98 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)812-826
Number of pages15
JournalGastroenterology
Volume153
Issue number3
DOIs
Publication statusPublished - Sep 1 2017

Fingerprint

Hepatocellular Carcinoma
CD274 Antigen
Neoplasms
T-Lymphocytes
Transcriptome
Chromosome Aberrations
Transforming Growth Factor beta
Exome
Mutation
Atlases
Neoplasm Antigens
Stromal Cells
Immunosuppression
Single Nucleotide Polymorphism
Melanoma
Lung Neoplasms
Genome
Pathology
Gene Expression
Survival

Keywords

  • Immune Checkpoint
  • Immune Regulation
  • Molecular Subgroups
  • Virtual Microdissection

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Sia, D., Jiao, Y., Martinez-Quetglas, I., Kuchuk, O., Villacorta-Martin, C., Castro de Moura, M., ... Llovet, J. M. (2017). Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features. Gastroenterology, 153(3), 812-826. https://doi.org/10.1053/j.gastro.2017.06.007

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

In: Gastroenterology, Vol. 153, No. 3, 01.09.2017, p. 812-826.

Research output: Contribution to journalArticle

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, SN, Mazzaferro, V, Esteller, M, Friedman, SL, Schwartz, M, Villanueva, A & Llovet, JM 2017, 'Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features', Gastroenterology, vol. 153, no. 3, pp. 812-826. https://doi.org/10.1053/j.gastro.2017.06.007
Sia D, Jiao Y, Martinez-Quetglas I, Kuchuk O, Villacorta-Martin C, Castro de Moura M et al. Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features. Gastroenterology. 2017 Sep 1;153(3):812-826. https://doi.org/10.1053/j.gastro.2017.06.007
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. / Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features. In: Gastroenterology. 2017 ; Vol. 153, No. 3. pp. 812-826.
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AU - Sia, Daniela

AU - Jiao, Yang

AU - Martinez-Quetglas, Iris

AU - Kuchuk, Olga

AU - Villacorta-Martin, Carlos

AU - Castro de Moura, Manuel

AU - Putra, Juan

AU - Camprecios, Genis

AU - Bassaganyas, Laia

AU - Akers, Nicholas

AU - Losic, Bojan

AU - Waxman, Samuel

AU - Thung, Swan N.

AU - Mazzaferro, Vincenzo

AU - Esteller, Manel

AU - Friedman, Scott L.

AU - Schwartz, Myron

AU - Villanueva, Augusto

AU - Llovet, Josep M.

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N2 - 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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