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Expression of Programmed Cell Death-Ligands in Hepatocellular Carcinoma: Correlation With Immune Microenvironment and Survival Outcomes
Haotian Liao1; Wen Chen2; Yunlu Dai3; Joseph J. Richardson4; Junling Guo5; Kefei Yuan6; Yong Zeng1,6; Kunlin Xie1
2019-09-11
Source PublicationFRONTIERS IN ONCOLOGY
ISSN2234-943X
Volume9
Abstract

The quantity of programmed cell death-ligand 1 (PD-L1) is regarded as a predicting factor of clinical response to anti-PD-1 axis immunotherapy. However, the expression of PD-L1 and its prognostic value in hepatocellular carcinoma (HCC) patients remain debated. Meanwhile, the molecular features of PD-1’s other ligand, namely PD-L2, as well as its correlation with clinicopathological parameters and HCC tumor microenvironment (TME), are still poorly understood. In this study, immunohistochemistry (IHC) data from 304 HCC patients were used to determine the clinicopathological features of PD-L1 and PD-L2 and their correlation with CD8+ T cells in HCC. Moreover, fresh clinical HCC samples were used to identify the immune cell subtypes expressing PD-L1 and PD-L2. By using The Cancer Genome Atlas (TCGA) dataset, we further assessed the correlation between mutation signature, copy number variation (CNV), number of neoepitopes, immune gene expression, immune/stromal cell infiltration to the expression of PD-L1 and PD-L2. While membrane expression of PD-L2 was observed in 19.1% of tumor samples, no obvious expression of PD-L1 was detected on tumor cell membranes. High expression of PD-L2 on tumor membranes and PD-L1 in immune stroma were both significantly associated with poorer overall survival (OS) and disease-free survival (DFS) outcomes. Flow cytometry analysis and immunofluorescence showed that macrophages were the main immune cell subtype expressing both PD-L1 and PD-L2. Moreover, positive expression of PD-Ls was correlated with higher CD8+ T cells infiltration in immune stroma. CNV analysis showed a similarity between PD-L1 and PD-L2 in affecting gene expression. In addition, higher levels of PD-Ls correlated with higher expression of immune related genes, enhanced cytolytic activity, and larger proportions of immune/stromal cell infiltration. Collectively, our study reveals the impact of both PDL1 and PD-L2 on the HCC tumor microenvironment for the first time, providing insight for new therapeutic options.

KeywordProgrammed Cell Death-ligands Macrophage Tumor Immune Stroma Tumor Microenvironment Antipd-1 Axis Therapy Hepatocellular Carcinoma
DOI10.3389/fonc.2019.00883
Indexed BySCI
Language英语
WOS Research AreaOncology
WOS SubjectOncology
WOS IDWOS:000485153900001
PublisherFRONTIERS MEDIA SA, AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
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Cited Times [WOS]:2   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorJunling Guo; Kefei Yuan; Yong Zeng
Affiliation1.Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
2.Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States
3.Faculty of Health Sciences, University of Macau, Macau, China
4.Department of Chemical and Biomolecular Engineering, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Parkville, VIC, Australia
5.John A. Paulson School of Engineering and Applied Sciences, Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, United States
6.Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
Recommended Citation
GB/T 7714
Haotian Liao,Wen Chen,Yunlu Dai,et al. Expression of Programmed Cell Death-Ligands in Hepatocellular Carcinoma: Correlation With Immune Microenvironment and Survival Outcomes[J]. FRONTIERS IN ONCOLOGY,2019,9.
APA Haotian Liao.,Wen Chen.,Yunlu Dai.,Joseph J. Richardson.,Junling Guo.,...&Kunlin Xie.(2019).Expression of Programmed Cell Death-Ligands in Hepatocellular Carcinoma: Correlation With Immune Microenvironment and Survival Outcomes.FRONTIERS IN ONCOLOGY,9.
MLA Haotian Liao,et al."Expression of Programmed Cell Death-Ligands in Hepatocellular Carcinoma: Correlation With Immune Microenvironment and Survival Outcomes".FRONTIERS IN ONCOLOGY 9(2019).
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