Hepatocellular Carcinoma Immunotherapy and the Potential Influence of Gut Microbiome

Abstract

Disruptions in the human gut microbiome have been associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. Evidence suggests that the gut microbiota can promote the development of hepatocellular carcinoma through the persistence of this inflammation by inducing genetic and epigenetic changes leading to cancer. As the gut microbiome is known for its effect on host metabolism and immune response, it comes as no surprise that the gut microbiome may have a role in the response to therapeutic strategies such as immunotherapy and chemotherapy for liver cancer. Gut microbiota may influence the efficacy of immunotherapy by regulating the responses to immune checkpoint inhibitors in patients with hepatocellular carcinoma. Here, we review the mechanisms by which gut microbiota influences hepatic carcinogenesis, the immune checkpoint inhibitors currently being used to treat hepatocellular carcinoma, as well as summarize the current findings to support the potential critical role of gut microbiome in hepatocellular carcinoma (HCC) immunotherapy.

Keywords: gut microbiome; hepatocellular carcinoma; immunotherapy; microbiota.

Figure 1

Mechanisms by which the gut microbiome plays a role in hepatocellular carcinoma. Besides the known risk factors for HCC, which include NAFLD, HBV, HCV, and alcohol, dysbiosis and leaky gut resulting from dysfunctional microbiota represent two other major factors leading to hepatic carcinogenesis. As such, several pathways are initiated, leading to HCC, which are detailed above. HCC: hepatocellular carcinoma; CLD: chronic liver disease; NAFLD: non-alcoholic fatty liver disease; HCV: hepatitis C virus; HBV: hepatitis B virus; MAMPs: microbiota-associated molecular patterns; TLR: toll-like receptor; LPS: lipopolysaccharide; LTA: lipoteichoic acid; SASP: senescence-associated secretory phenotype; DCA: deoxycholic acid; NKT: natural killer T cell; LSECs: liver sinusoidal cells; mTOR: mammalian target of rapamycin; CXCL-16: CXC motif ligand 16.