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Page 2 of 13 Kwee et al. Hepatoma Res 2021;7:8 I http://dx.doi.org/10.20517/2394-5079.2020.124

with estimated one-year survival rates of 21% for those with regionally advanced disease and 6% for
[1]
those with metastatic disease . After a decade of meager advances in systemic therapy, the treatment
of unresectable advanced-stage HCC has taken a leap forward with the advent of immune checkpoint
inhibitor (ICI) antibodies. In the United States, the first ICI agent to gain regulatory approval for HCC was
the anti-programmed death 1 (anti-PD1) monoclonal antibody nivolumab. Accelerated approval for this
ICI as a second-line systemic agent for HCC came after a 20% objective response rate was reported in the
dose expansion phase of its phase I/II trial (CheckMate-040) that involved patients who were refractory
[3]
to, or intolerant of, sorafenib . Pembrolizumab, another anti-PD1 antibody, also received accelerated
approval as a second-line therapeutic after similar response rates were reported in a non-randomized
open-label phase II clinical trial (KEYNOTE-224) . Most recently, a regimen combining bevacizumab
[4]
with atezolizumab, an anti-programmed death ligand 1 (PD-L1) antibody, received clinical approval as
a first-line systemic therapy for unresectable HCC, based on its phase III trial (IMbrave150) reporting
an objective response rate of 36%, along with better overall survival compared with sorafenib, the prior
[5]
standard of care .

Notwithstanding the hope that immunotherapy brings to patients with advanced HCC, all trials to
date have shown substantial heterogeneity in the degree to which tumors respond to these immune-
oncology agents. In the recently completed double-blind placebo-controlled randomized phase III trial of
pembrolizumab (KEYNOTE-240), only 2% of treated patients experienced a complete response (CR), while
[6]
16% and 32% experienced partial response (PR) and disease progression (PD), respectively . These results
mirror closely what was reported in the phase II trial of pembrolizumab (CR in 1%, PR in 16%, and PD in
33%) . Similarly, in the CheckMate-040 trial of nivolumab, 1%, 18%, and 32% of patients experienced CR,
[4]
[3]
PR, and PD, respectively . This degree of heterogeneity in tumor response has since been recapitulated in
[7,8]
observational cohorts of HCC patients receiving IC therapy . The observational data also suggest that
[7]
heterogeneity in tumor response translates into heterogeneity in survival outcome . Clinical response has
also been heterogeneous in the first-line treatment setting, with the IMbrave150 trial reporting 5.5% CR,
[5]
21.8% PR, and 19.8% PD in Child-Pugh class A patients not previously treated with sorafenib . Durations
of clinical response are also highly variable, ranging 6-24 (median 17) months in the CheckMate-040 trial
[3,9]
and 1.5-23.6 (median 13.8) months in the KEYNOTE-240 trial . Since immune-related adverse events
can be serious, a predictive biomarker that can adequately explain this heterogeneity across patients would
be of great benefit in the clinical setting for optimizing patient selection.

Unfortunately, no clinical trial to date has identified a reliable tissue or serum biomarker to predict
immunotherapy response in HCC. Although tumor PD-L1 expression has been associated with anti-
PD1/PD-L1 ICI response in multiple cancers (including non-small cell lung, bladder, cervical, and triple-
negative breast cancer), this immunohistochemical marker has not yet proven to be a good predictor of
[3,4]
response for HCC . Furthermore, while high microsatellite instability (MSI-H) and tumor mutation
burden (TMB) have been shown to be predictive of clinical immunotherapy response in multiple other
[8]
cancers, they have not proven very predictive of ICI response in HCC . It is therefore time to start looking
beyond these immediate immunotherapy biomarkers. Examining what is known about the underlying
mechanisms of tumor immune evasion in HCC and other cancers may help facilitate a broader search for
immunotherapy biomarkers that are useful for HCC.

ONCOGENIC MECHANISMS OF TUMOR IMMUNE EVASION LEADING TO POOR
IMMUNOTHERAPY RESPONSE
Multiple lines of mechanistic and clinical research have identified potential associations between tumor
immunotherapy resistance and well-known oncogenic pathways and mechanisms [10-18] . Of these, the Wnt/
b-catenin signaling pathway was among the earliest to be associated with tumor immune suppression [13,19] .