Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells

Abstract

Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types. The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma (HCC). Nevertheless, current immunotherapeutic approaches induce durable responses in only a subset of HCC patients. Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation, development, and progression of HCC, it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer. The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial, viral, and fungal antigens through the gut-liver axis. Here, we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them. We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.

Keywords: HCC; immunotherapy; innate immunity; tumor microenvironment.

Fig. 1

Timeline of US FDA approval of systemic HCC treatments^,,,,,–

Fig. 2

Current concepts for immunotherapy of HCC: TGF-βR1 TGF-beta receptor, IL-2 interleukin 2, aPD-1: anti-programmed cell death-1, aPD-L1 anti-programmed cell death ligand 1, aCTLA-4 anti-cytotoxic T-lymphocyte associated protein 4, aTIM-3 anti-T-cell immunoglobulin and mucin domain-containing protein 3, aLAG-3 anti-lymphocyte activation gene 3, TKI tyrosine kinase inhibitor, aVEGF anti-vascular endothelial growth factor, ICI immune checkpoint inhibitor, RT radiotherapy, TACE transarterial chemoembolization, SIRT selective internal radiation therapy, RFA radiofrequency ablation, anti-GPC3 anti-glypican-3, GV1001, AFP alpha-fetoprotein, CAR-T cell chimeric antigen receptor T cell, JX-594 pexastimogene devacirepvec oncolytic virus, p53MVA modified vaccinia ankara (MVA) virus-expressing p53 transgene

Fig. 3

Immune cell composition of the liver in homeostasis. NK cell natural killer cell, NKT cell natural killer T cell, MAIT mucosal-associated invariant T cell, ILC innate lymphoid cell, LSEC liver sinusoidal endothelial cell, Treg regulatory T cell, TCR T-cell receptor