Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities

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Abstract

Incidence of hepatocellular carcinoma (HCC) is on the rise due to the prevalence of chronic hepatitis and cirrhosis. Although there are surgical and chemotherapy treatment avenues the mortality rate of HCC remains high. Immunotherapy is currently the new frontier of cancer treatment and the immunobiology of HCC is emerging as an area for further exploration. The tumor microenvironment coexists and interacts with various immune cells to sustain the growth of HCC. Thus, immunosuppressive cells play an important role in the anti-tumor immune response. This review will discuss the current concepts of immunosuppressive cells, including tumor-associated macrophages, marrow-derived suppressor cells, tumor-associated neutrophils, cancer-associated fibroblasts, and regulatory T cell interactions to actively promote tumorigenesis. It further elaborates on current treatment modalities and future areas of exploration.

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The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation

Kankana Bardhan, Theodora Anagnostou, Vassiliki Boussiotis (2016)

The immune system maintains a critically organized network to defend against foreign particles, while evading self-reactivity simultaneously. T lymphocytes function as effectors and play an important regulatory role to orchestrate the immune signals. Although central tolerance mechanism results in the removal of the most of the autoreactive T cells during thymic selection, a fraction of self-reactive lymphocytes escapes to the periphery and pose a threat to cause autoimmunity. The immune system evolved various mechanisms to constrain such autoreactive T cells and maintain peripheral tolerance, including T cell anergy, deletion, and suppression by regulatory T cells (TRegs). These effects are regulated by a complex network of stimulatory and inhibitory receptors expressed on T cells and their ligands, which deliver cell-to-cell signals that dictate the outcome of T cell encountering with cognate antigens. Among the inhibitory immune mediators, the pathway consisting of the programed cell death 1 (PD-1) receptor (CD279) and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) plays an important role in the induction and maintenance of peripheral tolerance and for the maintenance of the stability and the integrity of T cells. However, the PD-1:PD-L1/L2 pathway also mediates potent inhibitory signals to hinder the proliferation and function of T effector cells and have inimical effects on antiviral and antitumor immunity. Therapeutic targeting of this pathway has resulted in successful enhancement of T cell immunity against viral pathogens and tumors. Here, we will provide a brief overview on the properties of the components of the PD-1 pathway, the signaling events regulated by PD-1 engagement, and their consequences on the function of T effector cells.

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Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma

David Kung-Chun Chiu, Aki Tse, Iris Xu … (2017)

Myeloid-derived suppressor cells (MDSCs) possess immunosuppressive activities, which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade. Here we report hypoxia as a cause of MDSC accumulation. Using hepatocellular carcinoma (HCC) as a cancer model, we show that hypoxia, through stabilization of hypoxia-inducible factor-1 (HIF-1), induces ectoenzyme, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2/CD39L1), in cancer cells, causing its overexpression in HCC clinical specimens. Overexpression of ENTPD2 is found as a poor prognostic indicator for HCC. Mechanistically, we demonstrate that ENTPD2 converts extracellular ATP to 5′-AMP, which prevents the differentiation of MDSCs and therefore promotes the maintenance of MDSCs. We further find that ENTPD2 inhibition is able to mitigate cancer growth and enhance the efficiency and efficacy of immune checkpoint inhibitors. Our data suggest that ENTPD2 may be a good prognostic marker and therapeutic target for cancer patients, especially those receiving immune therapy.

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Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma.

Firouzeh Korangy, Lars A. Ormandy, Heiner Wedemeyer … (2005)

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with a poor prognosis and one for which immunotherapy remains a viable option. Experimental tumor models have shown that regulatory T cells, a functionally unique subset of T cells, can suppress effective antitumor immune responses. This suppression might explain the poor outcome of some of the immunotherapy protocols currently being used. A better understanding of the role of regulatory T cells in HCC is important for design of future immunotherapy-based clinical protocols. We have studied regulatory T cells from 84 patients with HCC and 74 controls, including healthy donors, patients with chronic hepatitis B virus and hepatitis C virus infection and nonviral liver cirrhosis. Regulatory T cells were identified by fluorescence-activated cell sorting using a panel of antibodies and by real-time PCR analysis for Foxp3 expression. Functional studies were done to analyze their inhibitory role. Finally, regulatory T cells were analyzed in tumors and ascites from patients with HCC. Patients with HCC have increased numbers of CD4+CD25+ regulatory T cells in their peripheral blood, which express high levels of HLA-DR, GITR, and low or no CD45RA. These cells were anergic toward T-cell receptor stimulation and, when cocultured with activated CD4+CD25- cells, potently suppressed their proliferation and cytokine secretion. There were also high numbers of regulatory T cells in tumor-infiltrating lymphocytes of HCC patients comparable with the increase in their peripheral blood. Our data suggest that the increase in frequency of regulatory T cells might play a role in modulation of the immune response against HCC and could be important in design of immunotherapeutic approaches.

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Author and article information

Contributors

Xuehao Wang: wangxh@njmu.edu.cn

Ziyi Chen: dr_czy@126.com

Weiwei Tang: 1243773473twww@sina.com

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 29 August 2019

Publication date PMC-release: 29 August 2019

Publication date Collection: 2019

Volume: 18

Electronic Location Identifier: 130

Affiliations

[1 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Department of General Surgery, Nanjing First Hospital, , Nanjing Medical University, ; Nanjing, Jiangsu China

[2 ]ISNI 0000 0004 1799 0784, GRID grid.412676.0, Hepatobiliary/Liver Transplantation Center, , The First Affiliated Hospital of Nanjing Medical University, ; Nanjing, Jiangsu China

[3 ]GRID grid.477246.4, Key Laboratory of Living Donor Transplantation, , Chinese Academy of Medical Sciences, ; Nanjing, Jiangsu China

[4 ]ISNI 0000 0004 1936 8227, GRID grid.25073.33, Michael G. DeGroote School of Medicine, , McMaster University, ; Hamilton, Ontario Canada

[5 ]ISNI 0000 0004 1761 0489, GRID grid.263826.b, Department of General Surgery, Zhongda Hospital, Medical School, , Southeast University, ; Nanjing, Jiangsu China

Article

Publisher ID: 1047

DOI: 10.1186/s12943-019-1047-6

PMC ID: 6714090

PubMed ID: 31464625

SO-VID: 41fcc8c7-2228-44ad-8b9b-890060ce676b

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 27 April 2019

Date accepted : 18 July 2019

Funding

Funded by: National Natural Science Key Foundation of China

Award ID: 81530048

Award Recipient : Xuehao Wang

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hepatocellular carcinoma,macrophages,myeloid suppressor cells,immunotherapy

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hepatocellular carcinoma, macrophages, myeloid suppressor cells, immunotherapy

Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities

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Most cited references 80

The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation

Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma

Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma.

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