Abstract
Tumor immune escape is a common process in the tumorigenesis of non-small cell lung cancer (NSCLC) cells where programmed death ligand-1 (PD-L1) expression, playing a vital role in immunosuppression activity. Additionally, epidermal growth factor receptor (EGFR) phosphorylation activates Janus kinase-2 (JAK2) and signal transduction, thus activating transcription 3 (STAT3) to results in the regulation of PD-L1 expression. Chemotherapy with commercially available drugs against NSCLC has struggled in the prospect of adverse effects. Nobiletin is a natural flavonoid isolated from the citrus peel that exhibits anti-cancer activity. Here, we demonstrated the role of nobiletin in evasion of immunosuppression in NSCLC cells by Western blotting and real-time polymerase chain reaction methods for molecular signaling analysis supported by gene silencing and specific inhibitors. From the results, we found that nobiletin inhibited PD-L1 expression through EGFR/JAK2/STAT3 signaling. We also demonstrated that nobiletin exhibited p53-independent PD-L1 suppression, and that miR-197 regulates the expression of STAT3 and PD-L1, thereby enhancing anti-tumor immunity. Further, we evaluated the combination ability of nobiletin with an anti-PD-1 monoclonal antibody in NSCLC co-culture with peripheral blood mononuclear cells. Similarly, we found that nobiletin assisted the induction of PD-1/PD-L1 blockade, which is a key factor for the immune escape mechanism. Altogether, we propose nobiletin as a modulator of tumor microenvironment for cancer immunotherapy.
Highlights
To determine the evasion of immunosuppression effect of nobiletin, we first analyzed the inhibition of programmed death ligand-1 (PD-L1) expression by nobiletin in non-small cell lung cancer (NSCLC) cells—A549, H292 and H460
We found the inhibition of phospho-STAT3 and PD-L1 expression in NSCLC cells by nobiletin treatment, suggesting the possible role of miR-197 in the inhibition of STAT3 and PD-L1 by nobiletin. miRNA analysis showed that the addition of nobiletin increased the fold change of miR-197 to non-treated control cells (Figure 6A)
We found that a natural flavonoid inhibited the expression levels of PD-L1 in A549, H292 and H460 NSCLC cells
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Lung cancer is one of the most important cancer types, which constitutes an 18% death rate worldwide. Non-small cell lung cancer (NSCLC) is a subdivision of lung cancer that has recently recorded a survival rate of around 15% [1,2]. Patients who suffer from NSCLC struggle with specific chemotherapeutic drugs due to drug resistance and target specificity. This chemotherapy option results in some serious side effects [3,4]
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