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]
AbstractBackground 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.
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http://dx.doi.org/10.1136/gutjnl-2018-316510
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发表于 2018-7-7 09:47