Inhibition of NF‐κB is required for oleanolic acid to downregulate PD‐L1 by promoting DNA demethylation in gastric cancer cells

Lu, Xirong; Li, Yuyi; Yang, Wei; Tao, Minghao; Dai, Yanmiao; Xu, Jing

doi:10.1002/jbt.22621

Cited by 22 publications

(15 citation statements)

References 30 publications

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“…Sophoridine inhibits M2-TAM polarization via the TLR4/IRF3 axis, increases CD8 + T proliferation and cytotoxic function, and downregulates the expression of CD8 + T cell exhaustion markers PD-1, Tim-3, and Lag-3 ( 152 ). Oleanolic acid can promote the balance of Treg/Th17 cells in GC by targeting IL-6 through miR-98-5p, and is a potential drug for the treatment of GC ( 153 , 154 ).…”

Section: Immunotolerance Targeting Therapies In Gcmentioning

confidence: 99%

Tumor microenvironment-mediated immune tolerance in development and treatment of gastric cancer

Liu

et al. 2022

Front. Immunol.

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Tumor microenvironment is the general term for all non-cancer components and their metabolites in tumor tissue. These components include the extracellular matrix, fibroblasts, immune cells, and endothelial cells. In the early stages of tumors, the tumor microenvironment has a tumor suppressor function. As the tumor progresses, tumor immune tolerance is induced under the action of various factors, such that the tumor suppressor microenvironment is continuously transformed into a tumor-promoting microenvironment, which promotes tumor immune escape. Eventually, tumor cells manifest the characteristics of malignant proliferation, invasion, metastasis, and drug resistance. In recent years, stress effects of the extracellular matrix, metabolic and phenotypic changes of innate immune cells (such as neutrophils, mast cells), and adaptive immune cells in the tumor microenvironment have been revealed to mediate the emerging mechanisms of immune tolerance, providing us with a large number of emerging therapeutic targets to relieve tumor immune tolerance. Gastric cancer is one of the most common digestive tract malignancies worldwide, whose mortality rate remains high. According to latest guidelines, the first-line chemotherapy of advanced gastric cancer is the traditional platinum and fluorouracil therapy, while immunotherapy for gastric cancer is extremely limited, including only Human epidermal growth factor receptor 2 (HER-2) and programmed death ligand 1 (PD-L1) targeted drugs, whose benefits are limited. Clinical experiments confirmed that cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), vascular endothelial growth factor receptor (VEGFR) and other targeted drugs alone or in combination with other drugs have limited efficacy in patients with advanced gastric cancer, far less than in lung cancer, colon cancer, and other tumors. The failure of immunotherapy is mainly related to the induction of immune tolerance in the tumor microenvironment of gastric cancer. Therefore, solving the immune tolerance of tumors is key to the success of gastric cancer immunotherapy. In this study, we summarize the latest mechanisms of various components of the tumor microenvironment in gastric cancer for inducing immune tolerance and promoting the formation of the malignant phenotype of gastric cancer, as well as the research progress of targeting the tumor microenvironment to overcome immune tolerance in the treatment of gastric cancer.

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Section: Immunotolerance Targeting Therapies In Gcmentioning

confidence: 99%

Tumor microenvironment-mediated immune tolerance in development and treatment of gastric cancer

Liu

et al. 2022

Front. Immunol.

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“…In another study, after treating GC cells with compound oleanolic acid (OA), the expression specificity of DNA demethylase TET3 decreased and expression of downstream interleukin-1β (IL-1 β) was downregulated, so is PD-L1. In this process, DNA demethylase TET3, as an important mechanistic molecule, can largely restore the effect of OA on PD-L1 ( 31 ). Upregulation of MHC class I and MHC class II by DNA methyltransferases inhibitors (DNMTi) has appeared in many cancers ( 32 ).…”

Section: Regulatory Mechanism Of Pd-l1 In Gcmentioning

confidence: 99%

PD-L1: Biological mechanism, function, and immunotherapy in gastric cancer

et al. 2022

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Gastric cancer (GC) is one of the main causes of cancer incidence rate and mortality worldwide. As the main breakthrough direction, the application of immune checkpoint inhibitors makes patients with GC have better prognosis, where PD-L1/PD-1 inhibitors in immunotherapy have good anti-tumor immune efficacy. Further understanding of the regulatory mechanism of PD-L1 in GC may bring substantial progress to the immunotherapy. In this review, we provide information on the endogenous and exogenous regulatory mechanisms of PD-L1 and its biological functions combined with current clinical trials of PD-L1/PD-1 inhibitors in GC. The malignant biological phenotypes caused by PD-L1 and the corresponding clinical combined treatment scheme have been reported. Identifying the biomarkers of the potential efficacy of immunotherapy and specifying the clinical immunotherapy scheme in combination with molecular characteristics of patients may maximize clinical benefits and better prognosis.

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“…DNA methylation is mainly catalyzed by a family of DNMTs (168). In addition, 5-azacytidine, as a DNMT inhibitor, can increase PD-L1 expression in gastric cancer MKN-45 cells, whereas gemcitabine, a DNA demethylation inhibitor, can inhibit PD-L1 expression in these cells (169). Chondrosarcomas do not typically express PD-L1 to act as an immune-cold tumor; however, DNMT inhibitors can induce PD-L1 protein expression (73).…”

Section: Regulation Of Pd-l1 Expression In Solid Tumors By Dna Methyl...mentioning

confidence: 99%

Epigenetic modifications: Critical participants of the PD‑L1 regulatory mechanism in solid tumors (Review)

Wang

et al. 2022

Int J Oncol

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Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis have achieved marked and durable efficacy in patients with different solid tumors and have improved their survival. However, the presence of primary or acquired resistance to immune checkpoint blockades results in only a small fraction of patients benefiting from the treatment. An increasing number of preclinical studies have reported that PD-L1 expression in tumor cells is involved in a number of epigenetic changes, including histone modifications, non-coding RNA regulation and DNA methylation. In addition, multiple epigenetic targeting drugs have been demonstrated to directly or indirectly interfere with PD-L1 expression in various cancer models. This provides opportunities to better characterize the regulatory mechanisms of PD-L1 expression and explore novel therapeutic strategies to improve immunosuppressant response rates and overcome drug resistance. The present review focuses on the latest findings and evidence on the epigenetic mechanism regulating PD-L1 expression and discusses the biological and clinical implications of this regulatory mechanism in solid tumors. A rational combination of epigenetic regulation and PD-1/PD-L1 axis blockade may improve the prognosis of patients with solid tumors.

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Inhibition of NF‐κB is required for oleanolic acid to downregulate PD‐L1 by promoting DNA demethylation in gastric cancer cells

Cited by 22 publications

References 30 publications

Tumor microenvironment-mediated immune tolerance in development and treatment of gastric cancer

Tumor microenvironment-mediated immune tolerance in development and treatment of gastric cancer

PD-L1: Biological mechanism, function, and immunotherapy in gastric cancer

Epigenetic modifications: Critical participants of the PD‑L1 regulatory mechanism in solid tumors (Review)

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