From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) ranks the most common primary liver malignancy and the third leading cause of tumor-related mortality worldwide. Unfortunately, despite advances in HCC treatment, less than 40% of HCC patients are eligible for potentially curative therapies. Recently, cancer immunotherapy has emerged as one of the most promising approaches for cancer treatment. It has been proven therapeutically effective in many types of solid tumors, such as non-small cell lung cancer and melanoma. As an inflammation-associated tumor, it's well-evidenced that the immunosuppressive microenvironment of HCC can promote immune tolerance and evasion by various mechanisms. Triggering more vigorous HCC-specific immune response represents a novel strategy for its management. Pre-clinical and clinical investigations have revealed that various immunotherapies might extend current options for needed HCC treatment. In this review, we provide the recent progress on HCC immunology from both basic and clinical perspectives, and discuss potential advances and challenges of immunotherapy in HCC.

Keywords: Adoptive cell transfer; Hepatocellular carcinoma (HCC); Immune checkpoint blockade (ICB); Immunotherapy; Oncolytic virus.

Fig. 1

The landscape of immunosuppressive tumor microenvironment of HCC. Diverse suppressive immune cell subsets infiltration, regulatory secretions and some inhibitory signaling mediate HCC immune evasion. (Notes: Tregs: regulatory T cells; TAMs: tumor-associated macrophages; TANs: tumor associated neutrophils; CTLs:cytotoxic T lymphocytes; CAF: cancer associated fibroblast; MDSCs: myeloid- derived suppressor cells; HSCs: hepatic stellate cells; NK: natural killer cell; KC: Kupffer cell)

Fig. 2

Modulator role of NK cells in regulating HCC immune responses. NK cells exert multiple immune regulatory functions in HCC. Apart from the direct influences on tumor cells, interactions between NK cells and other immune cells or tumor stromal components have been demonstrated to mediate HCC immune evasion

Fig. 3

Current immunotherapeutic options for HCC. Immunotherapeutic approaches for HCC mainly include immune-checkpoint blockade (ICB), cell-based (mainly refers to DCs) /non-cell based vaccines, adoptive cell transfer (ACT), cytokine/antibody based immune regimens and oncolytic virus

Fig. 4

Oncolytic viruses based immunotherapy in HCC. Oncolytic viruses (OVs) selectively replicate in and damage tumor cells, subsequently spread in tumor tissue