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Page 2 of 13 da Fonseca et al. Hepatoma Res 2019;5:37 I http://dx.doi.org/10.20517/2394-5079.2019.012

INTRODUCTION
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related morbimortality and represents a
major health problem worldwide. HCC is ranked as the sixth most incident neoplasm and the fourth cause
[1]
of cancer-related death .

Remarkable progresses have been achieved in prevention, early detection and diagnosis. Concurrently, new
therapeutic strategies have been developed both in localized and advanced stages, what is leading to a more
favorable outcome for HCC patients comparing to the past decades. However, the field is continuously
evolving, and important barriers need to be surpassed.

In a significant proportion of cases, HCC is diagnosed at later stages and more than half of the patients
[2]
with localized disease will develop disease recurrence after locoregional treatments . At present, systemic
treatment options are limited. Only a few drugs have showed survival improvement according to phase
III trials. In 2008, sorafenib was the first drug that proved survival benefit according to the results of two
[3,4]
[5]
pivotal trials . A decade later, lenvatinib proved non-inferiority to sorafenib as a first-line option. In
[6]
[7]
[8]
the second-line setting, regorafenib , cabozantinib and ramucirumab demonstrated positive results in
placebo-controlled studies. Despite the incorporation of these new agents, the median survival of advanced
[9]
HCC patients treated with systemic treatment still remains around 2 years and there exists an unmet
need for innovative approaches.
One of the most notable advances in oncology over the last years is the use of immunotherapy, alongside
with an increasing knowledge on how the immune system behaves during carcinogenesis and tumor
progression. The idea to harness the immune system against cancer comes from the late 19th century.
Based on observations that some patients presented tumor remission after developing erysipelas, William
Coley proposed to inject a mixture of live and inactivated bacteria into in vivo tumors. Although there was
not a clear explanation at that time, anti-tumor responses were achieved in different types of tumors with
[10]
this intervention . In 1957, Thomas and Burnet proposed the theory of immunosurveillance, in which
[11]
lymphocytes played a role of sentinels to detect and destroy transformed cells . Afterwards, in the decade
of 1970s, the use of tuberculosis vaccine with Bacille Calmette-Guérin was effective in preventing recurrence
[12]
of urothelial carcinomas and is still applied nowadays . In 1990s, interleukin (IL)-2 was approved for
treatment of kidney cancer and melanoma. In the same decade, the first anti-CD20 monoclonal antibody,
[13]
named rituximab, was approved for non-Hodgkin lymphoma .

Currently, we are experiencing emerging trends in immunotherapy for treatment of several solid tumors,
including HCC. The scope of this review is to summarize the current landscape, updates and future
perspectives of immunotherapy in HCC.

RATIONALE FOR IMMUNOTHERAPY IN HCC
HCC arises in a chronically inflamed background in the vast majority of cases. An underlying liver disease
[14]
derived from a viral infection or from a non-infectious condition occurs in around 90% of HCC patients .
The immunologic composition of the liver is crucial for the role of this organ in the entero-hepatic
[15]
circulation as it exerts an immunologic control function under physiological condition .

Liver has an important function in host defense and self-tolerance by the coordinated activity of a diverse
immune-cell repertoire. Liver sinusoidal endothelial cells regulates the effector immune response by
inhibiting CD4+ and CD8+ T lymphocytes, thus preventing an immune reaction against bacterial antigens
coming from the gut. Moreover, these cells express high levels of Program death receptor ligand 1 (PD-L1),
which is a transmembrane immunosuppressive protein that inactivates the adaptative immune system by
binding to the inhibitory lymphocyte receptor PD-1 .
[16]