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Missale et al. Hepatoma Res 2018;4:22 I http://dx.doi.org/10.20517/2394-5079.2018.72 Page 9 of 15

risk of immune-related adverse events. The development of biomarkers with acceptable predictive value will
be instrumental to maximize the benefit of immunotherapy.

As previously described, the anti-cancer immune response is the results of multiple factors deriving from
the antigenic characteristics of the tumor, the multiplicity and the phenotype of TAA-specific immune cells,
the latter mainly dictated by the tumor microenvironment. From this perspective the use of a single analyte
biomarker might not be sufficient to recapitulate the complex interplay between tumor biology and immune
response. Immunostaining with anti-PD-L1 antibodies has been the first approach evaluated to predict the
response to anti-PD-1 treatments. However, this marker was shown to be unreliable especially for its poor
negative predictive value [139,140] . In addition, the intrinsic variability of immunohistochemistry together with
the heterogeneity and dynamic nature of PD-L1 expression in tumor and immune cells raise concern about
its adequacy to clinical standards [141] .

Multianalyte profiles may represent promising tools for the accurate prediction of immunotherapy outcome.
The response to PD-1 blockade has been related to the presence of immunogenic neoantigens arising from
the active expression of viral genes or from increased tumor mutational burden [140,142] . According to this
view, pembrolizumab (anti-PD-1) was approved by FDA in 2017 for the treatment of unresectable or meta-
static solid tumors with mutations in genes for DNA mismatch repair (dMMR) or microsatellite instability
(MSI), independently from the tissue of origin. However, dMMR or MSI are infrequent in HCC [143] .

The multiplicity, composition, activity and location of tumor-infiltrating immune cells have been shown
to represent prognostic markers in HCC [4-6,104] . A subset of HCCs characterized by an inflammatory gene
signature has been detected in several studies [144-148] . A recent study identified in about 25% of patients an
immune-specific molecular class of HCC including two distinct subtypes, characterized by a prevalent adap-
tive T-cell response and an exhausted immune response, respectively [146] . Interestingly, immune gene profiles
suggesting active anti-tumoral response have been associated with longer time to recurrence [149,150] .

Gene signatures may provide a global picture of the complex tumor immune landscape. This approach rep-
resents a tool for the discrimination of tumors with pre-existing immune infiltrate, more likely to respond to
interventions aimed at overcoming inhibitory factors. In a recent paper a so-called “T cell-inflamed gene ex-
pression profile”, containing IFN-γ-responsive genes related to antigen presentation, chemokine expression,
cytotoxic activity, and adaptive immune resistance, was shown to be necessary, but not always sufficient, for
clinical response to pembrolizumab in 10 tumor types [151] .

The lack or low abundance of cellular infiltrate may indicate a defect in innate immunity or in immune cell
trafficking and suggest alternative therapeutic approaches. Consistent with observations made in other tu-
mors [152] , a molecular profile of “immune exclusion” is associated with activated Wnt/β-catenin pathway sig-
naling in HCC [149] . This suggests the potential of Wnt/β-catenin activation as a biomarker predictive of resis-
tance to checkpoint inhibitors. As a future perspective, gene signatures integrating information about tumor
cell mutational burden, presence and nature of the immune infiltrate, possibly at different investigational
levels (genetic, genomic, epigenetic) would provide information for a comprehensive therapeutic stratifica-
tion of HCC patients.

DECLARATIONS
Authors’ contributions
The authors contributed equally to the conception, design, writing, and revision of this review article.

Availability of data and materials
Not applicable.