J Liver Cancer.  2020 Mar;20(1):1-16. 10.17998/jlc.20.1.1.

Deciphering and Reversing Immunosuppressive Cells in the Treatment of Hepatocellular Carcinoma

• Yu SJ
• Greten TF

• KMID: 2505837
• DOI: http://doi.org/10.17998/jlc.20.1.1

Abstract

Use of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) has been partially successful. However, most HCC patients do not respond to immunotherapy. HCC has been shown to induce several immune suppressor mechanisms in patients. These suppressor mechanisms include involvement of myeloid-derived suppressor cells, regulatory T-cells, functionally impaired dendritic cells (DCs), neutrophils, monocytes, and tumor associated macrophages. The accumulation of immunosuppressive cells may lead to an immunosuppressive tumor microenvironment as well as the dense fibrotic stroma which may contribute to immune tolerance. Our laboratory has been investigating different cellular mechanisms of immune suppression in HCC patients. In vitro as well as in vivo studies have demonstrated that abrogation of the suppressor cells enhances or unmasks tumor-specific antitumor immune responses. Two or three effective systemic therapies including ICIs and/or molecular targeted therapies and the addition of innovative combination therapies targeting immune suppressor cells may lead to increased immune recognition with a greater tumor response. We reviewed the literature for the latest research on immune suppressor cells in HCC, and here we provide a comprehensive summary of the recent studies in this field.

Keyword

Hepatocellular carcinoma; Immunotherapy; Immune checkpoint inhibitors; Immune suppression

Figure

• 

  Figure 1. Cross-talks among immune cells, immunosuppressive cells, stromal cells, and tumor cells in the tumor microenvironment of hepatocellular carcinoma. PDE, phosphodiesterase; STAT, signal transducer and activator of transcription; ATRA, all-trans-retinoic acid; MMP, matrix metalloproteinase; FU, fluorouracil; HSP, heat shock protein; MDSCs, myeloid-derived suppressor cells; GITR, glucocorticoid-induced TNFR family related gene; PD, programmed cell death protein; CTLA, cytotoxic T-lymphocyte-associated protein; CCR, cell cycle-related kinase; IL, interleukin; TAM, tumor associated macrophages; CCL, C-C motif chemokine ligand; CSF, stimulating factor; Treg, regulatory T-cells; PMN, polymorphonuclear; TAN, tumor-associated neutrophils; TGF, transforming growth factor; ARG, arginase; iNOS, inducible nitric oxide synthase; IDO, indoleamine 2,3-dioxygenase; DC, dendritic cells; NK, natural killer; CIK, cytokine-induced killer; TNFR, tumor necrosis factor receptor.

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