Published online Mar 21, 2018. doi: 10.3748/wjg.v24.i11.1228
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
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.
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].
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.
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.
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.
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.
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.