Original ResearchFull Report: Basic and Translational—LiverIdentification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features
Section snippets
Patients and Samples
For the purpose of the study, gene expression profile from a total of 956 HCC human samples was analyzed (Figure 1), including a training cohort of 228 surgically resected fresh frozen (FF) samples (Heptromic dataset, GSE63898). All samples of the training set were previously obtained from 2 institutions of the HCC Genomic Consortium upon institutional review board approval: IRCCS Istituto Nazionale Tumori (Milan, Italy) and Hospital Clínic (Barcelona, Spain). RNA profiling and methylation data
A Novel Immune Class of HCC
To isolate immune-related genomic signals from bulk gene expression data in HCC tumors, we performed NMF analysis of 228 resected HCC samples (training cohort, Figure 1). Clinical characteristics of the training cohort are summarized in Table 1. Among the distinct expression patterns identified by NMF, one was attributed to the presence of inflammatory response and immune cells through integration with a previously reported immune enrichment score (Supplementary Figure 1A). Analysis of the
Discussion
Our study represents a comprehensive characterization of the immunologic profile of human HCC tumors. The use of virtual separation analytical approaches enabled us to deconvolute the gene expression signals deriving from the intratumoral immune infiltrates; this identified a previously unnoticed robust class of HCC (∼27% of 956 patients), herein named Immune class. The immune nature of our classifier is supported by the overlap with gene signatures identifying immune cells (ie, T cells and
Acknowledgments
We thank Prof Jessica Zucman-Rossi for her advice and revision of the paper. We thank Wei Quiang Leow and Agrin Moeini for their support. The results shown here are in part based on data generated by the TCGA Research Network: http://cancergenome.nih.gov/.
References (42)
- et al.
Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010
Lancet
(2012) - et al.
Genetic landscape and biomarkers of hepatocellular carcinoma
Gastroenterology
(2015) - et al.
Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial
Lancet
(2017) - et al.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial
Lancet
(2016) - et al.
Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial
Lancet
(2017) - et al.
Hallmarks of cancer: the next generation
Cell
(2011) - et al.
Molecular and genetic properties of tumors associated with local immune cytolytic activity
Cell
(2015) - et al.
Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade
Cell Rep
(2017) - et al.
Transforming growth factor beta-mediated suppression of antitumor T cells requires FoxP1 transcription factor expression
Immunity
(2014) - et al.
Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis
Gastroenterology
(2013)
Hepatocellular carcinoma
Nat Rev Dis Primers
Sorafenib in advanced hepatocellular carcinoma
N Engl J Med
Advances in targeted therapies for hepatocellular carcinoma in the genomic era
Nat Rev Clin Oncol
PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations
Sci Transl Med
Pembrolizumab for the treatment of non-small-cell lung cancer
N Engl J Med
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer
N Engl J Med
An immune-active tumor microenvironment favors clinical response to ipilimumab
Cancer Immunol Immunother
PD-1 Blockade in tumors with mismatch-repair deficiency
N Engl J Med
Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation
Cancer Discov
Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity
Nature
Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma
Nat Genet
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Conflicts of interest The authors disclose the following: DS, AV, and JML are co-inventors of the patent “Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features” (Application N62/519,711). The remaining authors disclose no conflicts.
Funding This project has received funding from the Tisch Cancer Institute at Mount Sinai (P30 CA196521–Cancer Center Support Grant). J.M.L. is supported by grants from the US Department of Defense (CA150272P3), European Commission Framework Program 7 (HEPTROMIC, proposal number 259744), and Horizon 2020 Program (HEPCAR, proposal number 667273–2), the Asociación Española Contra el Cáncer, Samuel Waxman Cancer Research Foundation, Spanish National Health Institute (SAF2013–41027), and Grup de Recerca Consolidat–Recerca Translacional en Oncologia Hepàtica, AGAUR (Generalitat de Catalunya), SGR 1162. I.M.-Q. is supported by the European Commission HEPCAR grant. O.K. is supported by Onlus Prometeo, Hepato-Oncology Research Project, Istituto Nazionale Tumori (National Cancer Institute) IRCCS Foundation (Milan, Italy). L.B. is supported by the Juan de la Cierva Fellowship. V.M. is supported by grants from Associazione Italiana per la Ricerca sul Cancro and the Oncology Research Project of the Italian Ministry of Health. S.L.F. is supported by the US Department of Defense (CA150272P3) and National Institutes of Health (R01DK56621). A.V. is supported by the US Department of Defense (CA150272P3), The Tisch Cancer Institute, and the American Association for the Study of Liver Diseases Foundation Alan Hofmann Clinical and Translational Award.
Gene Expression Omnibus accession number: GSE93647, and previously deposited data from our group (GSE63898, GSE20140) and others [GPL1528, GSE1898, GPL2094 a), GPL80b), GPL96 E-TABM-36, GPL5474, GSE10186].
Author names in bold designate shared co-first authorship.