Epigenetic mechanisms of liver tumor resistance to immunotherapy

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver tumor, which stands fourth in rank of cancer-related deaths worldwide. The incidence of HCC is constantly increasing in correlation with the epidemic in diabetes and obesity, arguing for an urgent need for new treatments for this lethal cancer refractory to conventional treatments. HCC is the paradigm of inflammation-associated cancer, since more than 80% of HCC emerge consecutively to cirrhosis associated with a vast remodeling of liver microenvironment. In the recent decade, immunomodulatory drugs have been developed and have given impressive results in melanoma and later in several other cancers. In the present review, we will discuss the recent advancements concerning the use of immunotherapies in HCC, in particular those targeting immune checkpoints, used alone or in combination with other anti-cancers agents. We will address why these drugs demonstrate unsatisfactory results in a high proportion of liver cancers and the mechanisms of resistance developed by HCC to evade immune response with a focus on the epigenetic-related mechanisms.

Keywords: Liver cancer; Immunotherapies; Epigenetics; Resistance; Hepatocellular carcinoma

Core Tip: Although our understanding of hepatocellular carcinoma (HCC) pathogenesis has improved, this aggressive tumor is still devoid of effective treatments and remains a major health problem. Despite the justified hopes on immunotherapies, only a limited number of HCC patients respond to treatments. The characterization of the molecular mechanisms displayed by tumor cells to evade immune response will help to consider new combinations of therapies. In recent years, a growing body of evidence argues for a modulation of tumor immune privilege by several epigenetic events and renders drugs targeting these regulators as a partner of choice for immunotherapy combination strategies.