Antitumor Effects of Ursolic Acid through Mediating the Inhibition of STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer Cells.
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ABSTRACT:
SUBMITTER: Kang DY
PROVIDER: S-EPMC7998465 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Multiple clinical trials have shown that monoclonal antibodies (mAbs) against programmed death-ligand 1 (PD-1/PD-L1) can benefit patients with lung cancer by increasing their progression-free survival and overall survival. However, a significant proportion of patients do not respond to anti-PD-1/PD-L1 mAbs. In the present study, we investigated whether galectin (Gal)-3 inhibitors can enhance the antitumor effect of PD-L1 blockade. Using the NSCLC-derived cell line A549, we examined the expression of Gal-3 in lung cancer cells under hypoxic conditions and investigated the regulatory effect of Gal-3 on PD-L1 expression, which is mediated by the STAT3 pathway. We also explored whether Gal-3 inhibition can facilitate the cytotoxic effect of T cells induced by PD-L1 blockade. The effects of combined use of a Gal-3 inhibitor and PD-L1 blockade on tumor growth and T-cell function were also investigated, and we found that hypoxia increased the expression and secretion of Gal-3 by lung cancer cells. Gal-3 increased PD-L1 expression via the upregulation of STAT3 phosphorylation, and administration of a Gal-3 inhibitor enhanced the effect of PD-L1 blockade on the cytotoxic activity of T cells against cancer cells in vitro. In a mouse xenograft model, the combination of a Gal-3 inhibitor and PD-L1 blockade synergistically suppressed tumor growth. Furthermore, the administration of a Gal-3 inhibitor enhanced T-cell infiltration and granzyme B release in tumors. Collectively, our results show that Gal-3 increases PD-L1 expression in lung cancer cells and that the administration of a Gal-3 inhibitor as an adjuvant enhanced the antitumor activity of PD-L1 blockade.
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Project description:Background:Thymosin ?1 (T?1) is one of the most commonly used immunomodulators for metastatic non-small-cell lung cancer (NSCLC) patients in many countries. Despite the identification of the direct suppression on cancer cell proliferation, little is known about its effect on metastasis and metastasis-related signaling such as matrix metalloproteinases (MMPs) and programmed cell death ligand 1 (PD-L1). Materials and methods:NSCLC cells with distinguishing PD-L1 expression levels were treated with T?1. siRNAs were used to knockdown PD-L1. Cell migration and invasion abilities were evaluated by wound-healing and transwell assays. The xenograft model by BALB/c nude mice was constructed to test the inhibitory effect of T?1 on metastasis in vivo. The expression levels of metastasis-related signaling pathways and key molecules were assessed by Western blot (WB) and quantitative reverse transcriptase PCR (qRT-PCR). Results:T?1 significantly suppressed cell migration and invasion in PD-L1 high-expressing H1299, NL9980, and L9981 cells but not in PD-L1 low-expressing A549 or SPC-A-1 cells. This difference was demonstrated by mouse model in vivo as well. Knocking down of PD-L1 significantly impaired the inhibition of cell migration and invasion caused by T?1 treating in PD-L1 high-expressing cells. Besides, T?1 inhibited the activation and translocation of STAT3 and the expression of MMP2 in PD-L1 high-expressing NSCLC cells. Moreover, the treatment of STAT3 activator colivelin could partly reverse the T?1-induced MMP2 suppression and the migration phenotype. Conclusion:T?1 significantly suppresses migration and invasion in PD-L1 high-expressing NSCLC cells compared with PD-L1 low-expressing NSCLC cells in vitro and in vivo, through the downregulation of STAT3-MMP2 signaling. These different responses to T?1, together with the depiction of T?1-induced signaling changes, suggest a potential benefit of T?1 for PD-L1-positive NSCLC patients, enlightening the combination of T?1 with target therapy or immune checkpoint inhibitors.
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Project description:Lung cancer is the leading cause of cancer death in males and the second leading cause of death in females worldwide. Non-small-cell lung cancer (NSCLC) is the main pathological type of lung cancer, and most newly diagnosed NSCLC patients cannot undergo surgery because the disease is already locally advanced or metastatic. Despite chemoradiotherapy and targeted therapy improving clinical outcomes, overall survival remains poor. Immune checkpoint blockade, especially blockade of programmed death-1 (PD-1) receptor and its ligand PD-L1, achieved robust responses and improved survival for patients with locally advanced/metastatic NSCLC in preclinical and clinical studies. However, with regard to PD-1/PD-L1 checkpoint blockade as monotherapy or in combination with other antitumor therapies, such as chemotherapy, radiotherapy (including conventional irradiation and stereotactic body radiotherapy), and target therapy, there are still many unknowns in treating patients with NSCLC. Despite this limited understanding, checkpoint blockade as a novel therapeutic approach may change the treatment paradigm of NSCLC in the future. Here we review the main results from completed and ongoing studies to investigate the feasibility of PD-1/PD-L1 inhibitors, as monotherapy or combinatorial agents in patients with locally advanced and metastatic NSCLC, and explore optimal strategy in such patients.
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Project description:Aurora A plays a critical role in G2/M transition and mitosis, making it an attractive target for cancer treatment. Aurora A inhibitors showed remarkable antitumor effects in preclinical studies, but unsatisfactory outcomes in clinical trials have greatly limited their development. In this study, the Aurora A inhibitor alisertib upregulated programmed death ligand 1 (PD-L1) expression in a panel of tumor cells both in vitro and in vivo. Upregulation of the checkpoint protein PD-L1 reduced antitumor immunity in immune-competent mice, paradoxically inhibiting the antitumor effects of alisertib. Mechanistically, Aurora A directly bound to and phosphorylated cyclic GMP-AMP synthase (cGAS), suppressing PD-L1 expression in tumor cells. Aurora A inhibition by alisertib activated the cGAS/stimulator of IFN genes (STING)/NF-κB pathway and promoted PD-L1 expression. Combining alisertib with anti-PD-L1 antibody improved antitumor immunity and enhanced the antitumor effects of alisertib in immune-competent mice. Our results, which reveal the immunomodulatory functions of Aurora A inhibitors and provide a plausible explanation for the poor clinical outcomes with their use, offer a potential approach to improve the antitumor efficacy of these inhibitors.
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Project description:Programmed cell death ligand-1 (PD-L1) has recently gained considerable attention for its role in tumor immune escape. Here, we identify a miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer (NSCLC), independent of immunoinhibitory signals. miR-197 is downregulated in platinum-resistant NSCLC specimens, resulting in the promotion of chemoresistance, tumorigenicity, and pulmonary metastasis in vitro and in vivo. Mechanistic investigations reveal that a miR-197-mediated CKS1B/STAT3 axis exerts tumor progression regulated by various oncogenic genes (Bcl-2, c-Myc, and cyclin D1), and PD-L1 is a putative biomarker of this axis. Furthermore, we demonstrate that a miR-197 mimic sensitizes PD-L1(high) drug-resistant cells to chemotherapy. These results indicate that the biological interaction between PD-L1 and chemoresistance occurs through the microRNA regulatory cascade. More importantly, expression levels of miR-197 are inversely correlated with PD-L1 expression (n = 177; P = 0.026) and are associated with worse overall survival (P = 0.015). Our discoveries suggest that the miR-197/CKS1B/STAT3-mediated network can drive tumor PD-L1 expression as a biomarker of this cascade, and miR-197 replacement therapy may be a potential treatment strategy for chemoresistant NSCLC.
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Project description:In recent years, immunotherapy has revolutionized and changed the standard of care in patients with advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors, fundamentally those that act by blocking the programmed cell death receptor-1 (PD-1) and its ligand the programmed cell death ligand-1 (PD-L1) have emerged as novel treatment strategies in NSCLC, demonstrating undoubted superiority over chemotherapy in terms of efficacy. Several of these immune checkpoint modulators have recently gained regulatory approval for the treatment of advanced NSCLC, such as nivolumab, atezolizumab and pembrolizumab in first-line (only the latter) and second-line settings, and more recently, durvalumab as maintenance after chemoradiotherapy in locally advanced disease. There is consensus that PD-L1 expression on tumor cells predicts responsiveness to PD-1 inhibitors in several tumor types. Hence PD-L1 expression evaluated by immunohistochemistry (IHC) is currently used as a clinical decision-making tool to support the use of checkpoint inhibitors in NSCLC patients. However, the value of PD-L1 as the 'definitive' biomarker is controversial as its testing is puzzled by multiple unsolved issues such as the use of different staining platforms and antibodies, the type of cells in which PD-L1 is assessed (tumor versus immune cells), thresholds used for PD-L1-positivity, or the source and timing for sample collection. Therefore, newer biomarkers such as tumor mutation burden and neoantigens as well as biomarkers reflecting host environment (microbiome) or tumor inflamed microenvironment (gene expression signatures) are being explored as more reliable and accurate alternatives to IHC for guiding treatment selection with checkpoint inhibitors in NSCLC.
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Project description:Cancer immunotherapies have revolutionized the treatment of non-small cell lung cancer. Yet, only a small subset of patients will benefit from PD-1 or PD-L1 blockade. PD-L1 tumor cell expression is the only approved biomarker at present. Tumor mutational burden and other emerging biomarkers should improve patient selection. Combination therapy approaches with chemotherapy or cytotoxic T-lymphocyte-associated protein 4 blockade may increase the proportion of patients who benefit from immunotherapy. Although use of immunotherapy in lung cancers with targetable oncogenes has not been particularly successful, the benefit of PD-(L)1 inhibitors in early-stage disease is emerging. This review briefly describes the evolution of the clinical development and future directions of PD-(L)1 blockade in patients with lung cancers.
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Project description:The aim of the present study was to identify natural compounds that bear significant anti‑tumor activity. Thus, the effects of 63 small molecules that were isolated from traditional Chinese medicinal herbs on A549 human non‑small cell lung cancer (NSCLC) and MCF‑7 breast cancer cells were examined. It was found that ursolic acid (UA), a natural pentacyclic triterpenoid, exerted significant inhibitory effect on these cells. Further experiments revealed that UA inhibited the proliferation of various lung cancer cells, including the NSCLC cells, H460, H1975, A549, H1299 and H520, the human small cell lung cancer (SCLC) cells, H82 and H446, and murine Lewis lung carcinoma (LLC) cells. UA induced the apoptosis and autophagy of NSCLC cells. The inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, but not the activation of the extracellular signal‑regulated kinase 1/2 (ERK1/2) signaling pathway contributed to the UA‑induced autophagy of NSCLC cells. Moreover, the inhibition of autophagy by chloroquine (CQ) or siRNA for autophagy‑related gene 5 (ATG5) enhanced the UA‑induced inhibition of cell proliferation and promotion of apoptosis, indicating that UA‑induced autophagy is a pro‑survival mechanism in NSCLC cells. On the whole, these findings suggest that combination treatment with autophagy inhibitors may be a novel strategy with which enhance the antitumor activity of UA in lung cancer.
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Project description:BackgroundThe cisplatin-resistance is still a main course for chemotherapy failure of lung cancer patients. Cisplatin-resistant cancer cells own higher malignance and exhibited increased metastatic ability, but the mechanism is not clear. In this study, we investigated the effects of Ataxia Telangiectasia Mutated (ATM) on lung cancer metastasis.Materials and methodsCisplatin-resistant A549CisR and H157CisR cell line were generated by long-term treating parental A549 and H157 cells (A549P and H157P) with cisplatin. Cell growth, cell migration and cell invasion were determined. Gene expressions were determined by Western Blot and qPCR. Tumor metastasis was investigated using a xenograft mouse model.ResultsThe IC50 of the cisplatin-resistant cells (A549CisR and H157CisR cells) to cisplatin was 6-8 higher than parental cells. The A549CisR and H157CisR cells expressed lower level of E-cadherin and higher levels of N-cadherin, Vimentin and Snail compared to the parental A549P and H157P cells, and exhibited stronger capabilities of metastatic potential compared to the parental cells. The ATM expression was upregulated in A549CisR and H157CisR cells and cisplatin treatment also upregulated expression of ATM in parental cells, The inhibition of ATM by using specific ATM inhibitor CP466722 or knock-down ATM by siRNA suppressed Epithelial-to-Mesenchymal transition (EMT) and metastatic potential of A549CisR and H157CisR cells. These data suggest that ATM mediates the cisplatin-resistance in lung cancer cells. Expressions of JAK1,2,、 STAT3 、PD-L1 and ATM were increased in A549CisR and H157CisR cells and could by induced by cisplatin in parental lung cancer cells. Interestedly, ATM upregulated PD-L1 expression via JAK1,2/STAT3 pathway and inhibition of ATM decreased JAK/STAT3 signaling and decreased PD-L1 expression. The treatment of PD-L1 neutralizing Ab reduced EMT and cell invasion. Inhibition of JAK1,2/STAT3 signaling by specific inhibitors suppressed ATM-induced PD-L1 expression, EMT and cell invasion. Importantly, inhibition of ATM suppressed EMT and tumor metastasis in cisplatin-resistant lung cancer cells in an orthotopic xenograft mouse model.ConclusionsOur results show that ATM regulates PD-L1 expression through activation of JAK/STAT3 signaling in cisplatin-resistant cells. Overexpression of ATM contributes to cisplatin-resistance in lung cancer cells. Inhibition of ATM reversed EMT and inhibited cell invasion and tumor metastasis. Thus, ATM may be a potential target for the treatment of cisplatin-resistant lung cancer.
| S-EPMC6454747 | biostudies-literature