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Page 2 of 4 Kwee et al. Hepatoma Res 2022;8:32 https://dx.doi.org/10.20517/2394-5079.2022.58

Notable efforts had been made to identify predictive biomarkers within the cohorts of these and other HCC
immunotherapy trials. In the Keynote-040 trial, tumor PD-L1 immunohistochemical expression failed to
[1,3]
reliably predict objective response in those treated with nivolumab plus ipilimumab or nivolumab alone .
The phase 1b study of atezolizumab plus bevacizumab also found PD-L1 expression on tumor and tumor-
infiltrating immune cells to poorly predict progression-free survival . Furthermore, exploratory analyses
[5]
conducted using archival specimens from this and another early phase trial of atezolizumab plus
bevaciumab did not associate tumor mutation burden (TMB) with treatment response or progression-free
survival, although high expression of VEGF receptor 2, a T-regulatory signature, and a myeloid
inflammation signature were associated with benefit from atezolizumab plus bevacizumab compared with
[6]
atezolizumab alone . In a more recent extensive biomarker analysis for the IMbrave150 trial, high
expression of CD274 and intra-tumor CD8(+) cells density was associated with prolonged patient survival,
while high Treg:Teff ratio and expression of HCC tumor markers, such as GPC3 and AFP, were associated
[7]
with poor outcome . Although these results require further validation, they highlight the possibility of
using novel biomarkers to compensate for the lack of predictive value shown by PD-L1 expression and
TMB in HCC.

Much has recently been learned regarding the impact of underlying liver diseases and the liver immune
microenvironment on HCC immunotherapy outcome . Meta-analysis of three phase 3 randomized trials
[8,9]
(KEYNOTE-240, CheckMate 459, and IMBrave150) identified greater survival benefits among patients with
[10]
HCC of viral etiology compared to those with non-viral HCC . Furthermore, in a subgroup analysis of the
IMBrave150 trial, greater benefits were observed among Chinese patients, a group with an extremely high
prevalence of hepatitis B infection . Recently, non-alcoholic steatohepatitis (NASH), poised to become the
[11]
[12]
predominant cause of HCC in several parts of the world , has been associated with poor tumor response to
anti-PD1 antibody treatment based on rigorous experiments conducted using a NASH-associated HCC
[10]
animal model and corresponding retrospective analysis of clinical data . In addition, an updated analysis
of the IMBrave150 trial reported that the overall survival benefit in the atezolizumab-bevacizumab treated
sub-group with non-viral HCC was similar to those treated with sorafenib (HR: 1.05, 95%CI: 0.68-1.63),
although it should be pointed out that median progression-free survival and objective response rates
[4]
remained similar to the rest of the intention-to-treat population . Altogether, such observations suggest
that predictive modeling for individualizing HCC immunotherapy may need to factor in the underlying
cause of liver disease or include etiology-specific biomarkers.

While the earliest investigations into mechanisms of immune escape in HCC found aberrant Wnt/beta-
catenin pathway activation to be relatively common as a causative factor, additional tumor-intrinsic
mechanisms contributing to poor anti-tumor immunity have been described . Liquid biopsy platforms
[13]
based on hybridization capture such as Guardant360 CDx (Guardant Health, Redwood City, CA) and
FoundationOne Liquid CDx (Foundation Medicine, Cambridge, MA) hold the promise of a non-invasive
strategy for broadly assessing genomic alterations potentially tied to such mechanisms. First approved as
pan-cancer blood tests in the US in 2020, these platforms enable non-invasive multiplex characterization of
an increasing number of cancer-associated molecular alterations, including gene mutations, amplifications,
and rearrangements, in addition to potentially providing other generated biomarkers such as blood-based
tumor mutation burden and microsatellite instability. Because National Comprehensive Cancer Network
guidelines for HCC have, in effect, absolved clinicians from obtaining liver biopsies in patients who have a
high post-imaging test probability of HCC, there are fewer opportunities to procure tissue biomarkers in
HCC as compared to other cancers. This makes liquid biopsy attractive from a clinical standpoint as a
means to inform on the genomics of HCC. However, with regards to predicting immunotherapy response,
information from current cancer-targeted liquid biopsy panels may not suffice. It might need to be