Retrospective Cohort Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 21, 2018; 24(11): 1228-1238
Published online Mar 21, 2018. doi: 10.3748/wjg.v24.i11.1228
Role of relevant immune-modulators and cytokines in hepatocellular carcinoma and premalignant hepatic lesions
Abdel-Rahman N Zekri, Somaya El Deeb, Abeer A Bahnassy, Abeer M Badr, Mona S Abdellateif, Gamal Esmat, Hosny Salama, Marwa Mohanad, Ahmed Esam El-dien, Shimaa Rabah, Assmaa Abd Elkader
Abdel-Rahman N Zekri, Molecular Virology and Immunology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt
Somaya El Deeb, Abeer M Badr, Ahmed Esam El-dien, Shimaa Rabah, Assmaa Abd Elkader, Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt
Abeer A Bahnassy, Department of Pathology, National Cancer Institute, Cairo University, Cairo 11976, Egypt
Mona S Abdellateif, Medical Biochemistry and Molecular Biology, Department of Cancer Biology, National Cancer Institute, Cairo University, Cairo 11976, Egypt
Gamal Esmat, Hosny Salama, Department of Hepatology and Tropical Medicine, Faculty of Medicine, Cairo University, Cairo 11441, Egypt
Marwa Mohanad, Department of Biochemistry, Misr University for Science and Technology, 6th October 12945, Giza Governorate, Egypt
Author contributions: Zekri AN was the main supervisor, put forth the idea and planned of work, and performed data interpretation; El Deeb S supervised the biochemical work; Bahnassy AA supervised the flow cytometry work and revised the paper; Badr AM revised the paper; Abdellateif MS analyzed the data and wrote the paper; Esmat G and Salama H performed the medical care and the follow-up of patients; Mohanad M analyzed the data; El-dien AE performed the immunophenotyping; Rabah S and Abd Elkader A performed the ELISA work.
Institutional review board statement: The study was reviewed and approved for publication by our Institutional Reviewer.
Informed consent statement: All study participants or their legal guardian provided informed written consent about personal and medical data collection prior to study enrolment.
Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript.
Data sharing statement: The original anonymized dataset is available on request from the corresponding author at ncizekri@yahoo.com.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Abdel-Rahman N Zekri, MSc, PhD, Professor, Molecular Virology and Immunology Unit, Department of Cancer Biology, National Cancer Institute, Cairo University, Kasr Al-Aini Street, Fom El-Khaleeg, Cairo 11976, Egypt. ncizekri@yahoo.com
Telephone: +2-10-01413521 Fax: +2-202-23644720
Received: November 5, 2017
Peer-review started: November 6, 2017
First decision: November 27, 2017
Revised: December 24, 2017
Accepted: January 16, 2018
Article in press: January 16, 2018
Published online: March 21, 2018
Processing time: 130 Days and 19.8 Hours
ARTICLE HIGHLIGHTS
Research background

Hepatocellular carcinoma (HCC) is a major health problem worldwide and mainly in Egypt due to the high prevalence of hepatitis C virus (HCV) infection, especially of genotype IV. It ranks the first among cancers in males (33.6%), and the 2nd in females after breast cancer. Sorafenib is still the only treatment approved by the Food and Drug Administration for HCC; however, it extends the overall survival by 3 mo only. Hence, it is crucial to understand the underlying biological and immunological changes in HCC Egyptian patients, and to develop new treatment modalities based on these data.

Research motivation

The immune system plays an important role in suppression of cancer. However, tumors can escape immune surveillance by producing an immune-suppressive environment, for which the underlying mechanisms are not fully clear. Recent studies show that the immune response in HCC patients is usually down-regulated by immunosuppressive cells (myeloid-derived suppressor cells and T regulatory cells) that are involved in chronic inflammation and tumor progression. Also, these inhibitory cells secrete many immune-suppressive cytokines, such as interleukin (IL)-6, IL-10 and transforming growth factor-β, creating a tolerogenic and suppressive environment[9].

Research objectives

The objective of this study was to assess the levels of different immune modulators and cytokines that may play a role in the pathogenesis of HCC and other hepatic diseases (e.g., chronic hepatitis and liver cirrhosis) compared to a normal group. This would help in identifying additional therapeutic modalities for viral infections and HCC in the context of immunotherapy.

Research methods

This retrospective cohort study included 88 patients who attended the medical oncology clinics of the National Cancer Institute, Cairo University during the period from 2014 to 2016. Patients were divided into the HCC group (20 patients-G1), liver cirrhosis group (28 patients-G2), chronic hepatitis group (CH; 25 patients-G3) and normal healthy volunteers as a control group (NC; 15 persons). The immune system of the patients was assessed through immunophenotyping of CD1c and CD40, CD1c and HLA, CD303 and CD40, CD303 and HLA, CD56 and CD161, CD56 and CD314, and CD56 and CD158 by flow cytometry. On the other hand, serum levels of IL-2, IL-10, IL-12, IL-1β, interferon (IFN)-α, IFN-γ and tumor necrosis factor (TNF)-αR2 were measured by the ELISA technique, according to the manufacturer’s instructions. Data were expressed as mean ± SE of mean, and statistical comparison between cytokine levels and immune cells were performed.

Research results

There was a significant decrease in active and inactive mDCs in HCC patients compared to the NC group, as well as active mDCs (CD1C+/CD40+) in cirrhotic patients compared to CH patients. The expression level of CD40+ on active pDCs (CD303+) was significantly decreased in HCC compared to the NC. However, there was no significant difference with the other groups (cirrhosis and CH). Meanwhile, the level of inactive pDCs (CD303+/HLA+) and inactive NK cells (CD56+/CD158+) did not differ significantly between the four groups studied.

The active NK cells (CD56+/CD161+) showed a significant increase in the CH group, whereas the level of active NK cells (CD56+/CD314+) was statistically decreased in HCC, CH and cirrhotic patients compared to the NC group, indicating an important role of these cells in the pathogenesis of HCC. The individual expression of each cell type in patients showed that active NK cells (CD56+/CD314+) were not expressed in 63% (12/20) of HCC patients.

There was a significant decrease in serum levels of IL-2, IFN-α and IFN-γ in HCC patients compared to the NC group, and a significant increase in serum levels of IL-10, IL-1β and TNF-αR2 in HCC compared to the NC group. However, there was no statistically significant change in the serum level of IL-12 among the four groups studied.

Research conclusions

We conclude that there are immunological changes occurring in HCC patients in relation to other liver diseases. The related immunological factors are NKG2D expressed on NK cells, and pDCs expressing CD40, IL-2 and IL-10. These factors could be implicated in the pathogenesis of HCC, and represent attractive targets for therapeutics in chronic HCV hepatitis and liver cancer.

Research perspectives

NKG2D, CD40, IL-2 and IL-10 could be a possible candidate for future immunotherapy for HCC patients. However, further studies are recommended regarding correlation of these factors and clincopathological features as well as the overall survival of the patients.