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Shrestha et al. Hepatoma Res 2019;5:32 I http://dx.doi.org/10.20517/2394-5079.2019.24 Page 9 of 17
[68]
the therapy [28,52,67] . Johnson et al. have reported two cases of lethal myocarditis in melanoma patients
treated with combination of Nivolumab and Ipilimumab. In HCC, ICI monotherapy has shown some
tolerable adverse effects such as fatigue, rash, pruritus and increase of serum transaminases that could be
managed either by steroid therapy or discontinuation as there were no fatal adverse effects [20,35,52] . Several
other immune-related adverse events such as pulmonary, gastrointestinal, cardiac, rheumatologic, renal,
endocrine, neurologic and dermatologic toxicities have been reported in various cancers treated with
[69]
ICIs . The ideal management of adverse events is to identify these adverse events early with careful
monitoring and use of respective treatment options . Gastrointestinal toxicities including diarrhoea
[69]
have been managed with anti-motility agents such as loperamide, diphenoxylate/atropine or higher fibre
intake . Similarly, the possible liver toxicities post ICI therapy can be managed through liver function
[69]
[70]
tests prior to therapy followed by steroids and mycophenolate mofetil if necessary . These toxicities can be
rare in incidence but clinicians should monitor these events and act promptly for proper management .
[69]
Another important limitation of immune checkpoint blockade therapy is poor response to ICI therapy
whereby the patient fails to respond after the initial therapy or the patient develops resistance to ICI
following initial response . In hepato-pancreatic-biliary cancers, a majority of patients fail to respond to
[67]
[71]
ICI therapy . The failure of ICI therapy can result from three factors: (1) mutations of the immunogenicity
of cancer itself leading to variable expression of immune related components; (2) redundancy due to
expression of other immune checkpoint molecules besides the targeted molecule; and (3) decreased
[74]
T-cell infiltration [46,72,73] . A study by Gopalakrishnan et al. reported that the gut microbiome altered
melanoma patient response to anti PD-1 ICIs. Similarly, another study in liver cancer revealed that the gut
microbiome utilizes bile acid to regulate immune responses .
[75]
The expression of immune checkpoint molecules varies among individuals suggesting the need for
[28]
predictive biomarker to improve the efficacy of ICI therapy . The expression of PD-L1 and tumor-
infiltrating lymphocytes has been reported to be associated with success of ICI therapy . The FDA has
[28]
[76]
approved an IHC test for PD-L1 expression as a predictive biomarker . However, some patients with low
PD-L1 expression responded well to Nivolumab . There is need for more robust predictive biomarkers
[77]
for ICI therapy besides PD-L1 expression. Tumor mutation burden (TMB), a measure of the overall number
of mutations in the tumor specimen, has also been reported as a potential predictive biomarker in ICI
[25]
therapy . Moreover, overexpression of alternative immune checkpoint molecules such as TIM-3 and LAG-3
following anti-PD-1 therapy has been reported . In a clinical study of 422 HCC patients, although PD-L1
[72]
expression alone lacked predictive power, combining PD-L1 expression with epithelial-to-mesenchymal
transition (EMT) phenotype marker expression was associated with poor overall survival and recurrence-
[25]
free survival . As EMT has also been implicated as a resistance mechanism in patients undergoing ICI
treatments, a better understanding of this process may aid in overcoming resistance to ICI therapies.
Figure 1 summarizes the association between EMT and immune checkpoint regulation and also depicts
the EMT process as a main resistance mechanism to immune checkpoint blockade therapy.

ROLE OF EMT IN IMMUNE CHECKPOINT BLOCKADE THERAPY
EMT is a complex cellular process that enables epithelial cells to gain mesenchymal features resulting in
aggressive and motile phenotype . The EMT process enables cells to move distances and participate in
[78]
the formation of internal organs, while the reverse process mesenchymal-to-epithelial transition (MET)
enables cells to settle, proliferate and differentiate into different organs once they reach the destination [79-81] .
EMT is regulated by several factors including transcription factors such as Snail, Twist, zinc-finger E-box-
binding transcription factor, ZEB and others [78,82] . EMT is often induced by various cell signalling pathways
[83]
such as TGF-β, Wnt, STAT and NOTCH pathways . The process of EMT induces epithelial carcinoma
cells to transition to metastatic tumor cells such that tumor cells spread from their primary site to a new