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Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma
Chun Jye Lim1, Yun Hua Lee1, Lu Pan1, Liyun Lai1, Camillus Chua1, Martin Wasser1, Tony Kiat Hon Lim2,3, Joe Yeong2,4, Han Chong Toh3,5, Ser Yee Lee3,5,6, Chung Yip Chan3,5,6, Brian KP Goh3,5,6, Alexander Chung3,5,6, Mathias Heikenwälder7, Irene OL Ng8, Pierce Chow3,5,6, Salvatore Albani1, Valerie Chew1
Author affiliations
Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
Department of Pathology, Singapore General Hospital, Singapore, Singapore
Duke-NUS Medical School, Singapore, Singapore
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
National Cancer Centre, Singapore, Singapore
Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore, Singapore
Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
Correspondence to Dr Valerie Chew, Translational Immunology Institute, SingHealth- DukeNUS Academic Medical Centre, Singapore 169856, Singapore; [email protected]
Abstract
Background and aims Chronic inflammation induced by chronic hepatitis B virus (HBV) infection increases the risk of hepatocellular carcinoma (HCC). However, little is known about the immune landscape of HBV-related HCC and its influence on the design of effective cancer immunotherapeutics.
Methods We interrogated the immune microenvironments of HBV-related HCC and non-viral-related HCC using immunohistochemistry and cytometry by time-of-flight (CyTOF). On identifying unique immune subsets enriched in HBV-related HCC, we further interrogated their phenotypes and functions using next-generation sequencing (NGS) and in vitro T-cell proliferation assays.
Results In-depth interrogation of the immune landscapes showed that regulatory T cells (TREG) and CD8+ resident memory T cells (TRM) were enriched in HBV-related HCC, whereas Tim-3+CD8+ T cells and CD244+ natural killer cells were enriched in non-viral-related HCC. NGS of isolated TREG and TRM from HBV-related HCC and non-viral-related HCC identified distinct functional signatures associated with T-cell receptor signalling, T-cell costimulation, antigen presentation and programmed cell death protein 1 (PD-1) signalling. TREG and TRM from HBV-related HCC expressed more PD-1 and were functionally more suppressive and exhausted than those from non-virus-related HCC. Furthermore, immunosuppression by PD-1+ TREG could be reversed with anti-PD-1 blockade. Using multiplexed tissue immunofluorescence, we further demonstrated that TREG and TRM contributed to overall patient survival: TREG were associated with a poor prognosis and TRM were associated with a good prognosis in HCC.
Conclusion We have shown that the HBV-related HCC microenvironment is more immunosuppressive and exhausted than the non-viral-related HCC microenvironment. Such in-depth understanding has important implications in disease management and appropriate application of immunotherapeutics.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:http://creativecommons.org/licenses/by-nc/4.0/.
http://dx.doi.org/10.1136/gutjnl-2018-316510
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Significance of this study
What is already known on this subject?
The tumour microenvironment (TME) of HBV-related HCC has mostly been studied in the context of one particular immune subset or by comparing the HBV-related HCC with livers from patients with chronic HBV infection or healthy individuals.
A comprehensive and multidimensional analysis focusing on HBV-related HCC versus non-viral-related HCC is lacking.
What are the new findings?
We analysed the TME of HBV-related HCC in comparison to non-viral-related HCC using CyTOF and NGS.
We identified distinct immune subsets enriched in both HCC aetiologies, and found that the HBV-related HCC immune landscape consisted of more immunosuppressive and exhausted phenotypes.
TREG and rTRM that are enriched in HBV-related HCC are associated with overall patient survival in opposing directions.
How might it impact on clinical practice in the foreseeable future?
An in-depth understanding of the TME in HBV-related versus non-viral-related HCC will allow us to design rational combinatory immunotherapy specific for each aetiology.
Novel immunotherapeutics that target unique pathways in either HBV-related HCC or non-viral-related HCC could be designed for better disease management. |
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发表于 2019-4-9 16:35