Epigenetic modification-related mechanisms of hepatocellular carcinoma resistance to immune checkpoint inhibition

Abstract

Hepatocellular carcinoma (HCC) constitutes most primary liver cancers and is one of the most lethal and life-threatening malignancies globally. Unfortunately, a substantial proportion of HCC patients are identified at an advanced stage that is unavailable for curative surgery. Thus, palliative therapies represented by multi-tyrosine kinase inhibitors (TKIs) sorafenib remained the front-line treatment over the past decades. Recently, the application of immune checkpoint inhibitors (ICIs), especially targeting the PD-1/PD-L1/CTLA-4 axis, has achieved an inspiring clinical breakthrough for treating unresectable solid tumors. However, many HCC patients with poor responses lead to limited benefits in clinical applications, which has quickly drawn researchers' attention to the regulatory mechanisms of immune checkpoints in HCC immune evasion. Evasion of immune surveillance by cancer is attributed to intricate reprogramming modulation in the tumor microenvironment. Currently, more and more studies have found that epigenetic modifications, such as chromatin structure remodeling, DNA methylation, histone post-translational modifications, and non-coding RNA levels, may contribute significantly to remodeling the tumor microenvironment to avoid immune clearance, affecting the efficacy of immunotherapy for HCC. This review summarizes the rapidly emerging progress of epigenetic-related changes during HCC resistance to ICIs and discusses the mechanisms of underlying epigenetic therapies available for surmounting immune resistance. Finally, we summarize the clinical advances in combining epigenetic therapies with immunotherapy, aiming to promote the formation of immune combination therapy strategies.

Keywords: epigenetic modification; hepatocellular carcinoma (HCC); immune checkpoint inhibitors; immune resistance mechanisms; tumor immunotherapy.

Figure 1

The landscape of systemic therapy for HCC treatment strategies. (A) The guidelines are sorted out and summarized by 2018 ASCO, 2018 AASLD, and 2020 EASL. The clinical stages of the patients are defined according to BCLC. (B) Main drugs for systemic therapy. TKI, Multi-tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor; VEGF, vascular endothelial growth factor; ASCO, American Society of Clinical Oncology; AASLD, American Association for the Study of Liver Diseases; EASL, European Association for the Study of the Liver; BCLC, Barcelona Clinic Liver Cancer.

Figure 2

Representative clinical trials for the systemic treatment of HCC. Background color: red for trials with first-line settings, pink for trials with second-line settings, and purple for trials with negative results.

Figure 3

Schematic diagram of the molecular mechanism of impaired anti-tumor immunity caused by immune checkpoints and reactivation of T cells with PD-1/PD-L1 blocking antibody. When tumor cell PD-L1 binds to T cell PD-1, this interaction leads to T cell dysfunction and lack of anti-tumor activity. Thus, blocking the interaction between PD-1 and PD-L1 with anti-PD-1 or PD-L1 antibodies can reactivate T cells and release their anti-tumor activity.

Figure 4

Immunosuppressive TME of HCC. In the TME of HCC, there are cell types that promote anti-tumor immunity and cell types that impede effective immune surveillance, which are illustrated in this figure. Treg cell, regulatory T cell; MDSC, myeloid-derived suppressor cell; NK, natural killer; IDO, indoleamine 2,3-dioxygenase; VEFG, vascular endothelial growth factor; TGF-β, transforming growth factor-β.

Figure 5

The regulatory systems involved in the epigenetic landscape of HCC. The epigenetic marks in HCC include chromatin structure remodeling, DNA methylation, histone post-translational modification and non-coding RNA.

Figure 6

Typical histone post-translational modifications and DNA methylation mechanism. The figure shows the role of epigenetic regulation of chromatin by DNA methylation and histone post-translational modifications in the occurrence and development of HCC. The figure highlights the role of histone demethylase (HDM), histone methyltransferase (HMT), histone acetyltransferases (HAT), histone deacetylase (HDAC), and DNA methyltransferase (DNMT) in the formation of epigenetic characteristics of HCC. Ac, acetylation; Me, Methylation. The figure shows that EZH2 overexpression leads to elevated H3K27me3 levels on the promoters of CD274 and interferon regulatory factor 1 (IRF1), impeding PD-L1 expression. In, addition, the alteration caused by HDAC8 overexpression activates the Wnt/β-Catenin pathway, which in turn impairs antitumor immunity of antigen-specific T cells resulting in ICI resistance.

Figure 7

Mechanisms of combined epigenetic and immunotherapeutic strategies for HCC treatment. (A) Figure A illustrates the enhanced efficacy of DNMTi combined with ICIs by promoting immune cell activation and infiltration into TME and inducing hypermethylated silenced neoantigen expression. (B) Figure B demonstrates that HMTi combined with ICIs promotes immune cell activation and infiltration to TME and enhances NK cell-mediated HCC killing by upregulating the expression of chemokines, PD- L1, and NK cell ligand, which are inhibited by high histone methylation.