Current insights into the hepatic microenvironment and advances in immunotherapy for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and shows high global incidence and mortality rates. The liver is an immune-tolerated organ with a specific immune microenvironment that causes traditional therapeutic approaches to HCC, such as chemotherapy, radiotherapy, and molecular targeted therapy, to have limited efficacy. The dramatic advances in immuno-oncology in the past few decades have modified the paradigm of cancer therapy, ushering in the era of immunotherapy. Currently, despite the rapid integration of cancer immunotherapy into clinical practice, some patients still show no response to treatment. Therefore, a rational approach is to target the tumor microenvironment when developing the next generation of immunotherapy. This review aims to provide insights into the hepatic immune microenvironment in HCC and summarize the mechanisms of action and clinical usage of immunotherapeutic options for HCC, including immune checkpoint blockade, adoptive therapy, cytokine therapy, vaccine therapy, and oncolytic virus-based therapy.

Keywords: adoptive cell therapy; cancer immunotherapy; hepatocellular carcinoma; immunocheck point inhibitors; tumor microenvironment.

Figure 1

Schematic diagram of the landscape of the immune microenvironment in HCC. The infiltration of various subpopulations of immune cells, regulatory cytokines, and certain inhibitory signals mediate the specific immune response in HCC. The HCC tumor cells produce various factors, such as IDO, VEGF, IL-10, and hypoxia, to suppress the tumoricidal ability of CTL, and TGF-β, IL-10 and inhibitory receptors NKG2A, to suppress the tumoricidal ability of NK cells. Additionally, the HCC tumor cells secrete CXC chemokines, especially CXCL8, to attract TANs into the tumor stroma. The activation of PD-1 signaling in B cells promotes the production of IL-10, which inhibits the anti-tumor immunity of effector T cells. The crosstalk between MDSCs and TAMs results in a decreased secretion of IL-6 and IL-12, and an increased secretion of IL-10, which impair the cytotoxicity of CTL and NK cells. The aggregation of MDSCs in the tumor stroma is mediated by various cytokines, such as VEGF, IL-β, and IL-6 that produced by CAFs and HSCs, and VEGF and GM-CSF that produced by HCC tumor cells. MDSCs interact with KCs to induce PD-L1 expression on KCs, which interact with PD-1 on T cells to mediate immune evasion. Galectin-9 expression on MDSCs can bind to TIM-3 on T cells to induce T cell apoptosis. Tregs can inhibit CTL activation that mediated by reduced production of TNF-α and IFN-γ, and weaken the anti-tumor ability of NK cells through the production of IL-2, IL-8, and TGF-β. DCs can mediate IL-10 production and IL-12 reduction to suppress the antitumor response of CTL. CTL, cytotoxic T lymphocyte; NK, natural killer cells; TAM, tumor-associated macrophage; MDSC, myeloid-derived suppressor cell; TAN, tumor-associated neutrophil; CAF, cancer-associated fibroblast; HSC, hepatic stellate cell; KC, Kupffer cell; DC, dendritic cell; IDO, indoleamine 2,3-dioxygenase; VEGF, vascular endothelial growth factor; IL-10, interleukin-10; NKG2A, inhibitory receptors natural killer group 2A; TGF-β, transforming growth factor β; GM-CSF, granulocyte-macrophage colony-stimulating factor; ICI, immune checkpoint inhibitor. The figure was drawn at BioRender.com.

Figure 2

Schematic diagram of the current immunotherapeutic options for HCC. Immunotherapeutic approaches for HCC mainly include immune checkpoint blockade (ICB), adoptive cell therapy (ACT), cytokine based immune regimens, therapeutic vaccine and oncolytic virus. The figure was drawn at BioRender.com.