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Missale et al. Hepatoma Research 2018;4:22 Hepatoma Research
DOI: 10.20517/2394-5079.2018.72

Review Open Access

Time for hepatocellular carcinoma immunotherapy:
insights for successful clinical applications in this
challenging tumor

Gabriele Missale , Elisabetta Cariani 2
1
1 Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma,
Parma 43126, Italy.
2 Toxicology and Advanced Diagnostics, Ospedale Civile S. Agostino-Estense, Modena 41126, Italy.
Correspondence to: Dr. Gabriele Missale, Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda
Ospedaliero-Universitaria di Parma, Parma 43126, Italy. E-mail: missalegabriele@gmail.com

How to cite this article: Missale G, Cariani E. Time for hepatocellular carcinoma immunotherapy: insights for successful clinical
applications in this challenging tumor. Hepatoma Res 2018;4:22. http://dx.doi.org/10.20517/2394-5079.2018.72

Received: 1 Jun 2018 First Decision: 12 Jun 2018 Revised: 15 Jun 2018 Accepted: 19 Jun 2018 Published: 25 Jun 2018

Science Editor: Guang-Wen Cao Copy Editor: Jun-Yao Li Production Editor: Huan-Liang Wu

Abstract
The multiplicity and phenotype of intratumoral immune infiltrate have been shown to influence the clinical
outcome of hepatocellular carcinoma (HCC), thus providing a strong rationale to therapeutic interventions
aimed at restoring the dysfunctional immune response against the tumor. Improving the knowledge of the
complex interactions between transformed hepatocytes, nonparenchymal resident cells, and infiltrating immune
cells (characterizing the HCC microenvironment) will be instrumental to increase the success rate of existing
immunotherapeutic strategies and to identify new potential targets for intervention or biomarkers to optimize the
selection of candidate patients.

Keywords: Hepatocellular carcinoma, immune checkpoint inhibitors, T lymphocytes, cytotoxic T lymphocytes,
natural killer cells, macrophages, cytokines
b

INTRODUCTION
The liver immune landscape fosters tolerance towards foreign antigens driven by portal blood. Liver sinu-
soidal endothelial cells (LSECs) that separate liver parenchyma from sinusoidal blood, liver resident mac-
rophages (Kupffer cells), hepatic stellate cells (HSCs), and dendritic cells (DCs) exert antigen presenting cell
[1]
(APC) function and participate in the tolerogenic liver environment . Innate immune cells such as natural
killer (NK), NKT and γ/δ T cells are found at higher frequency in the liver, as Foxp3+ regulatory T cells
(Tregs). The liver environment is also characterized by increased expression of immunosuppressive cyto-
[2]
kines such as interleukin (IL)-10 and transforming growth factor (TGF)-β .
© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
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