Abstract
Liver cancer is the sixth most common cancer worldwide with high morbidity and mortality. Programmed death ligand 1 (PD-L1) is a major ligand of programmed death 1 receptor (PD1), and PD1/PD-L1 checkpoint acts as a negative regulator of the immune system. Cancers evade the host’s immune defense via PD-L1 expression. This study aimed to investigate the effects of tumor-related cytokines, interferon gamma (IFNγ), and tumor necrosis factor alpha (TNFα) on PD-L1 expression in human hepatocellular carcinoma cells, HepG2. Furthermore, as atorvastatin, a cholesterol-lowering agent, is documented for its immunomodulatory properties, its effect on PD-L1 expression was investigated. In this study, through real-time RT-PCR, Western blot, and immunocytochemistry methods, PD-L1 expression in both mRNA and protein levels was found to be synergistically upregulated in HepG2 by a combination of IFNγ and TNFα, and STAT1 activation was mainly responsible for that synergistic effect. Next, atorvastatin can inhibit the induction of PD-L1 by either IFNγ alone or IFNγ/TNFα combination treatment in HepG2 cells. In conclusion, in HepG2 cells, expression of PD-L1 was augmented by cytokines in the tumor microenvironment, and the effect of atorvastatin on tumor immune response through inhibition of PD-L1 induction should be taken into consideration in cancer patients who have been prescribed atorvastatin.
Highlights
Being the sixth most commonly diagnosed cancer and the third leading cause of cancer death in 2020, liver cancer has been imposing a significant burden on world health [1].hepatocellular carcinoma (HCC), the major form of primary liver cancer, is known for its progressiveness and poor prognosis
The difference between the effect of individual cytokine (IFNγ or tumor necrosis factor-α (TNFα)) and that of a combination of these two cytokines on programmed death ligand-1 (PD-L1) expression in HepG2 cells was determined in this study
MTT assay was performed at 24and 48-h period of treatment to find out the non-toxic dose of IFNγ and TNFα: either individual or combination treatment, in HepG2 cells (Figure 1A–C)
Summary
Being the sixth most commonly diagnosed cancer and the third leading cause of cancer death in 2020, liver cancer has been imposing a significant burden on world health [1]. Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is known for its progressiveness and poor prognosis. The majority of HCC patients are diagnosed at advanced stages when most therapeutic options such as transplant, surgery, or ablation are impractical [2]. Finding out newer treatment regimens has become a necessity, and immunotherapy is one of them. Progression of hepatocellular carcinoma is a multistep process in which inflammation plays a critical component, and many cytokines and chemokines take part in linking inflammation and cancer [3]. Inflammation-prone tumor microenvironment (TME) of HCC is associated with conditions favoring tumor immune tolerance such as the high ratio of
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