Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options

Abstract

The prevalence of liver cancer is constantly rising, with increasing incidence and mortality in Europe and the USA in recent decades. Among the different subtypes of liver cancers, hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer. Besides advances in diagnosis and promising results of pre-clinical studies, HCC remains a highly lethal disease. In many cases, HCC is an effect of chronic liver inflammation, which leads to the formation of a complex tumor microenvironment (TME) composed of immune and stromal cells. The TME of HCC patients is a challenge for therapies, as it is involved in metastasis and the development of resistance. However, given that the TME is an intricate system of immune and stromal cells interacting with cancer cells, new immune-based therapies are being developed to target the TME of HCC. Therefore, understanding the complexity of the TME in HCC will provide new possibilities to design novel and more effective immunotherapeutics and combinatorial therapies to overcome resistance to treatment. In this review, we describe the role of inflammation during the development and progression of HCC by focusing on TME. We also describe the most recent therapeutic advances for HCC and possible combinatorial treatment options.

Keywords: cancer therapy; hepatocellular carcinoma; immunotherapies; tumor microenvironment.

Figure 1

Crosstalk between the TME and HCC cells in the process of liver fibrosis and HCC development. The dynamic crosstalk between the non-cancer cells and cancer cells is crucial for the process of liver fibrosis and HCC development. Complex interactions influence cancer progression and result in inhibition of the anti-cancer response by activating and mobilizing immune cells with immunosuppressive properties. The inflammatory environment of HCC leads to upregulation of CCL2, which recruits monocytes to the tissue where they can differentiate into macrophages. LSECs stimulated by pathogen infections release the proinflammatory IL-6 and TNF-α, and initiate stem cell activation through PDGF release. The stemness of HCC cells is also supported by HGF secreted by CAFs. CAFs also promote tumorigenesis by expressing pro-angiogenic cytokines, such as VEGF and PDGF. Increased expression of CXCL11 by CAFs facilitates the recruitment of T cells into inflammatory sites, supporting the self-renewal of tumor-initiating cells. NK cell activation and cytotoxic activity is inhibited by PGE₂ and IDO enzymes produced by CAFs, and also by blocking of the NKp30 receptor by MDSCs. TAMs express the D48 ligand, which interacts with the 2B4 receptor on NK cells, causing their exhaustion and apoptosis. High levels of TGF-β enhance the expression of inhibitory receptors, including PD-1 and CTLA-4, on T cells, impairing their proliferation, differentiation, and activation. Additionally, the release of kynurenine, SAM, and MTA by cancer cells in the TME can lead to T cell exhaustion. Tregs promote immune tolerance against neoplastic cells by suppressing CTLs. Figure created with BioRender.com (accessed on 27 February 2022).