Tumor-Intrinsic Mechanisms Regulating Immune Exclusion in Liver Cancers

Abstract

Representing the fourth leading cause of cancer-related mortality worldwide, liver cancers constitute a major global health concern. Hepatocellular carcinoma (HCC), the most frequent type of liver cancer, is associated with dismal survival outcomes and has traditionally had few treatment options available. In fact, up until 2017, treatment options for advanced HCC were restricted to broad acting tyrosine kinase inhibitors, including Sorafenib, which has been the standard of care for over a decade. Since 2017, a multitude of mono- and combination immunotherapies that include pembrolizumab, nivolumab, ipilumumab, atezolizumab, and bevacizumab have been FDA-approved for the treatment of advanced HCC with unprecedented response rates ranging from 20 to 30% of patients. However, this also means that ~70% of patients do not respond to this treatment and currently very little is known regarding mechanisms of action of these immunotherapies as well as predictors of response to facilitate patient stratification. With the recent success of immunotherapies in HCC, there is a pressing need to understand mechanisms of tumor immune evasion and resistance to these immunotherapies in order to identify biomarkers of resistance or response. This will enable better patient stratification as well as the rational design of combination immunotherapies to restore sensitivity in resistant patients. The aim of this review is to summarize the current knowledge to date of tumor-intrinsic mechanisms of immune escape in liver cancer, specifically in the context of HCC.

Preneoplastic lesions in the liver: Molecular insights and relevance for clinical practice

“…In addition, c-myelocytomatosis (c-MYC) overexpression could play a role in immune evasion by upregulation of programmed cell death ligand 1 (PDL1) in neoplastic hepatocytes. 24,25 Furthermore, changes in the immune infiltration of the underlying liver have been described in the course of hepatic disease. In particular, an increase in cluster differentiation (CD) 8 + T cells was observed on cirrhosis in parallel to a decrease in CD4 + T cells, as well as an expansion of profibrogenic macrophages.…”

“…For example, activation of the β‐catenin pathway promotes immune evasion in HCC, with lower tumour enrichment of T cells and downregulation of CCL‐4 and CCL5 chemokines. In addition, c‐myelocytomatosis (c‐MYC) overexpression could play a role in immune evasion by upregulation of programmed cell death ligand 1 (PDL1) in neoplastic hepatocytes 24,25 . Furthermore, changes in the immune infiltration of the underlying liver have been described in the course of hepatic disease.…”

Application of Immunotherapy in Hepatocellular Carcinoma

“…Activation or alteration of some genes and signaling pathways may promote immune escape in HCC ( 19 ). For example, activation of β-Catenin ( 20 ) or mutation of CTNNB1 ( 21 ) may promote immune escape in HCC.…”

“…The combination of immune checkpoints and their respective ligands will inhibit the activation and proliferation of T cells. f. Activation or alteration of some genes and signaling pathways may promote immune escape in HCC (19). For example, activation of b-Catenin (20) or mutation of CTNNB1 (21) may promote immune escape in HCC.…”

The advanced development of molecular targeted therapy for hepatocellular carcinoma

“…Liver cancer is the fourth leading cause of cancer-associated death worldwide, accounting for more than 840,000 new cases and 780,000 deaths each year 1 , 2 . According to the World Health Organization, the number of deaths from liver cancer will exceed 1 million by 2030, thus posing a major threat to human health 3 . The 2 most frequent forms of liver cancer are hepatocellular carcinoma (HCC) and cholangiocarcinoma, which represent 85%–90% and 6%–15% of all primary liver cancers, respectively 4 , 5 .…”