Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Issue 5 (3rd July 2018)

• Record Type: Journal Article
• Authors: Lim, Chun Jye; Lee, Yun Hua; Pan, Lu; Lai, Liyun; Chua, Camillus; Wasser, Martin; Lim, Tony Kiat Hon; Yeong, Joe; Toh, Han Chong; Lee, Ser Yee; Chan, Chung Yip; Goh, Brian KP; Chung, Alexander; Heikenwälder, Mathias; Ng, Irene OL; Chow, Pierce; Albani, Salvatore; Chew, Valerie
• Is Part Of: Gut. Volume 68:Issue 5(2019)
• Page Start: 916
• Page End: 927
• Publication Date: 2018-07-03
• Subjects: hepatitis B -- hepatocellular carcinoma -- immunotherapy -- cancer immunobiology -- immunoregulation; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2018-316510
• Languages: English
• ISSNs: 0017-5749

Abstract

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.