Non-Invasive Biomarkers for Immunotherapy in Patients with Hepatocellular Carcinoma: Current Knowledge and Future Perspectives

Abstract

The treatment perspectives of advanced hepatocellular carcinoma (HCC) have deeply changed after the introduction of immunotherapy. The results in responders show improved survival compared with Sorafenib, but only one-third of patients achieve a significant benefit from treatment. As the tumor microenvironment exerts a central role in shaping the response to immunotherapy, the future goal of HCC treatment should be to identify a proxy of the hepatic tissue condition that is easy to use in clinical practice. Therefore, the search for biomarkers that are accurate in predicting prognosis will be the hot topic in the therapeutic management of HCC in the near future. Understanding the mechanisms of resistance to immunotherapy may expand the patient population that will benefit from it, and help researchers to find new combination regimens to improve patients' outcomes. In this review, we describe the current knowledge on the prognostic non-invasive biomarkers related to treatment with immune checkpoint inhibitors, focusing on serological markers and gut microbiota.

Keywords: PD-1; PD-L1; biomarkers; gut microbiota; hepatocellular carcinoma (HCC); immunotherapy; liquid biopsy.

Figure 1

Novel biomarkers for immunotherapy in patients with HCC. CtDNA and CTCs reflect tumor growth and invasiveness of HCC. Genome analysis of ctDNA allows for the detection of prognostic tumor mutations. CTC levels correlate with tumor extension and may have a role in predicting tumor recurrence after immunotherapy. EVs contain proteins, lipids, DNAs, mRNAs, miRNAs, and non-coding RNAs including circRNAs and lncRNAs. These products influence ICIs’ efficacy by down- or up-regulating PD-L1 expression in the tumor microenvironment. Immune system hyperstimulation by ICIs can lead to the production of ADA. ADA directed against ICIs promote immunocomplex formation and drug clearance, potentially affecting anti-tumor efficacy. The gut microbiota’s composition and products regulate several immune and metabolic pathways in the gut–liver axis, including the response to ICIs. Gut microbiota profiles differ among ICIs responders and non-responders, opening the field to studies testing microbiota-targeted therapies as a new strategy in immuno-oncology. In particular increased abundance of Akkermansia muciniphila, Klebsiella pneumoniae, Ruminococcaceae Lactobacilli, Bifidobacterium dentium, Streptococcus thermophilus, and Citrobacter freundii has been linked to response to immunotherapy; Firmicutes/Bacteroidetes ratio between 0.5 and 1.5 and a higher mean ratio of Prevotella spp. to Bacteroides spp. are also markers of improved survival, whereas increased abundance of Escherichia coli, Lactobacillus reuteri, Streptococcus mutans, Enterococcus faecium, and Veillonellales, and a reduction in bacterial diversity has been associated with non-response. ctDNA: circulating tumor DNA, CTCs: circulating tumor cells, EVs: extracellular vesicles, mRNAs: messenger RNAs, miRNAs: microRNAs, circRNAs: circular RNAs, lncRNAs: long non-coding RNAs, ICIs: immune checkpoint inhibitors, ADA: antidrug antibodies, and PD-L1: programmed death-ligand 1.