Immunotherapy for Hepatocellular Carcinoma: A 2021 Update

Abstract

Hepatocellular carcinoma (HCC) is one of one of the most frequent liver cancers and the fourth leading cause of cancer-related mortality worldwide. Current treatment options such as surgery, neoadjuvant chemoradiotherapy, liver transplantation, and radiofrequency ablation will benefit only a very small percentage of patients. Immunotherapy is a novel treatment approach representing an effective and promising option against several types of cancer. The aim of our study is to present the currently ongoing clinical trials and to evaluate the efficacy of immunotherapy in HCC. In this paper, we demonstrate that combination of different immunotherapies or immunotherapy with other modalities results in better overall survival (OS) and progression-free survival (PFS) compared to single immunotherapy agent. Another objective of this paper is to demonstrate and highlight the importance of tumor microenvironment as a predictive and prognostic marker and its clinical implications in immunotherapy response.

Keywords: adoptive cellular immunotherapy; cancer vaccines; hepatocellular carcinoma; immune checkpoint inhibitors; immunotherapy; microsatellite instability; oncolytic viruses; tumor microenvironment.

Figure 1

Hepatocellular carcinoma microenvironment. (A) Tumor microenvironment creates a barrier from extracellular matrix for immunotherapy as well as for cytotoxic drugs to act significantly in HCC. (B) Resistance mechanisms in HCC inducing tumor progression, immunosuppression, and cancer cell survival. Activation of Wnt/CTNNB1 signaling inhibits CCL5 production, thereby DC recruitment. Hypoxia and activation of HIF-1a promotes recruitment of MDSCs, Tregs, and TANs, whereas HCV infection and MDSCs promote T-cell apoptosis through activation of TIM3 receptor by Galectin-9 secretion by monocytes. HCC: hepatocellular carcinoma cells; ECM: extracellular matrix; TAM: tumor-associated macrophages; ΤAΝ: tumor-associated neutrophils; MDSCs: myeloid-derived suppressive cells; CTLs: cytotoxic T-lymphocytes; Tregs: CD4+ regulatory T cells; NKT cells: natural killer T cells; DC: dendritic cells IL: interleukin; TGF-β: transforming growth factor beta; IFNs: interferons; HiF1-a: hypoxia-inducible factor-1α; VEGF: vascular endothelial growth factor; CCL2: C-C motif chemokine ligand 2; CCL5: CC-chemokine ligand 5; CXCL12: C-X-C motif chemokine 12; CSF-1: colony stimulating factor 1; IFITM2: interferon-induced transmembrane protein 2.