PD-L1 expression is regulated by both DNA methylation and NF-kB during EMT signaling in non-small cell lung carcinoma

Asgarova, Afag; Asgarov, Kamal; Godet, Yann; Peixoto, Paul; Nadaradjane, Arulraj; Boyer-Guittaut, Michaël; Galaine, Jeanne; Guenat, David; Mougey, Virginie; Perrard, Jérôme; Pallandre, Jean-René; Bouard, Adeline; Balland, Jérémy; Tirole, Charline; Adotévi, Olivier; Hendrick, Elodie; Herfs, Michaël; Cartron, Pierre-François; Borg, Christophe; Hervouet, Éric

doi:10.1080/2162402x.2017.1423170

Cited by 165 publications

(167 citation statements)

References 54 publications

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“…Thus, PD-L1 promoter methylation may provide a potentially more effective immunotherapeutic strategy in some tumor patients. Since PD-L1 overexpression transiently occurs during the cytokine-driven epithelial mesenchymal transition (EMT), a strong link between PD-L1 promoter demethylation and the TGF-β signaling pathway was found, which was associated with the loss of DNA methyltransferase 1 (DNMT1) in lung cancer cells [96].…”

Section: Epigenetic Deregulation Of Pd-l1 In Tumorsmentioning

confidence: 99%

Basis of PD1/PD-L1 Therapies

Seliger

2019

JCM

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It is obvious that tumor cells have developed a number of strategies to escape immune surveillance including an altered expression of various immune checkpoints, such as the programmed death-1 receptor (PD-1) and its ligands PD-L1 and PD-L2. The interaction between PD-1 and PD-L1 results in an activation of self-tolerance pathways in both immune cells as well as tumor cells. Thus, these molecules represent excellent targets for T cell-based immunotherapies. However, the efficacy of therapies using checkpoint inhibitors is variable and only a limited number of patients receive a long-term response, while others develop resistances. Therefore, a better insight into the constitutive expression levels and their control as well as the predictive and prognostic value of PD-1/PD-L1, which are controversially discussed due to the methodological assessment, the dynamic and time-related variable expression of these molecules, is urgently required. In this review, the current knowledge of the PD-L1 and PD-1 genes, their expression in immune and tumor cells, the underlying molecular mechanisms of their regulation and their association with clinical parameters and therapy responses are summarized.

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Section: Epigenetic Deregulation Of Pd-l1 In Tumorsmentioning

confidence: 99%

Basis of PD1/PD-L1 Therapies

Seliger

2019

JCM

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“…Notably, certain studies have elucidated that in human melanoma, PD-L1 expression may be altered by DNA hypomethylating agents (29). Moreover, the expression level of PD-L1 can be regulated using DNA methylation, in response to NF-κB or transforming growth factor-β signaling in NSCLC (30). In the current study, the PD-L1 methylation status correlated with PD-L1 protein expression and the number of lymph node metastases, implying that methylation of the PD-L1 promoter may affect tumor progression in advanced gastric cancer tissues, via the regulation of protein expression.…”

Section: Pd-l1 Promoter Methylationmentioning

confidence: 99%

PD‑L1 gene promoter methylation represents a potential diagnostic marker in advanced gastric cancer

Xing

Cao

et al. 2019

Oncol Lett

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Gastric cancer is one of the most prevalent malignant tumors worldwide. Immunological checkpoint inhibitors of the programmed death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) signaling pathway are effective in the treatment of various malignant tumor types, but the potential of such immunotherapeutic techniques for the treatment of gastric cancer is yet to be elucidated. The purpose of the present study was to investigate the methylation of the PD-L1 gene promoter and its clinical significance in advanced gastric cancer, as this may suggest the use of PD-L1 promoter methylation as a novel biomarker for gastric cancer progression. In a total of 70 samples, the methylation rate of the PD-L1 gene promoter region was significantly higher in gastric cancer tissues compared with adjacent tissues. A high level of PD-L1 promoter methylation was associated with lymph node staging, and resulted in poorer prognoses in patients with advanced gastric cancer. A total of 26 patients exhibited highly methylated PD-L1; in this group, the median progression-free survival time of patients receiving platinum/fluorouracil chemotherapy was 4.2 months longer than those receiving paclitaxel/fluorouracil chemotherapy, and the risk of disease progression in patients receiving paclitaxel/fluorouracil chemotherapy was 5.009 times higher compared with patients who received platinum/fluorouracil chemotherapy. Additionally, PD-L1 promoter methylation was significantly correlated with PD-L1 expression, and the progression of advanced gastric cancer. In conclusion, high methylation levels of the PD-L1 promoter region may be a faciliatory mechanism enabling gastric cancer tumorigenesis, and may also represent an independent prognostic factor for chemotherapeutic efficacy in patients with advanced gastric cancer.

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“…These data indicate that increased expression of PDL1 with age most directly associates 18 with age-related increases in tumor mutational burden. 19 20 Due to previous work suggesting that DNA methylation regulates tumor expression of PDL1 21 (Asgarova et al, 2018), (Micevic et al, 2019), we hypothesize that the observed expression 22 increases of immune checkpoint genes are largely driven by epigenetic changes. We leverage 23 merged 450k and 27k methylation array data from TCGA (Thorsson et al, 2018) and find that 24 methylation of CpGs annotated to the PDL1 promoter region significantly decreases with age 25 pan-cancer (q = 3.27 x 10 -10 ), including cancer type as a covariate.…”

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confidence: 99%

Aging interacts with tumor biology to produce major changes in the immune tumor microenvironment

Erbe

Wang

Zaidi

et al. 2020

Preprint

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1Advanced age is strongly correlated with both increased cancer incidence and general immune 2 decline. The immune tumor microenvironment (ITME) has been established as an important 3 prognostic of both therapeutic efficacy and overall patient survival. Thus, age-related immune 4 decline is an important consideration for the treatment of a large subset of cancer patients. 5Current studies of aging-related immune alterations are predominantly performed on non-6 cancerous tissue, requiring additional study into the effects of age on tumor immune infiltration. 7We leverage large scale transcriptional data sets from The Cancer Genome Atlas and the 8 Genotype-Tissue Expression project to distinguish normal age-related immune alterations from 9 age-related changes in tumor immune infiltration. We demonstrate that while there is overlap 10 between the normal immune aging phenotype and that of the ITME, there are several changes 11 in immune cell abundance that are specific to the ITME, particularly in T cell, NK cell, and 12Macrophage populations. These results suggest that aged immune cells are more susceptible to 13 tumor suppression of cytotoxic immune cell infiltration and activity than normal tissues, which 14 creates an unfavorable ITME in older patients in excess of normal immune decline with age and 15 may inform the application of existing and emerging immunotherapies for this large population 16 of patients. We additionally identify that age-related increases in tumor mutational burden are 17 associated with decreased DNA methylation and increased expression of the immune 18 checkpoint genes PDL1, CD80, and LAG3 which may have implications for therapeutic 19 application of immune checkpoint blockade in older patients. 20 21

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PD-L1 expression is regulated by both DNA methylation and NF-kB during EMT signaling in non-small cell lung carcinoma

Cited by 165 publications

References 54 publications

Basis of PD1/PD-L1 Therapies

Basis of PD1/PD-L1 Therapies

PD‑L1 gene promoter methylation represents a potential diagnostic marker in advanced gastric cancer

Aging interacts with tumor biology to produce major changes in the immune tumor microenvironment

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