DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer

Nair, Varun Sasidharan; Salhat, Haytham El; Taha, Rowaida Z.; John, Anne; Ali, Bassam R.; Elkord, Eyad

doi:10.1186/s13148-018-0512-1

Cited by 102 publications

(103 citation statements)

References 63 publications

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“…11 Recently, we have reported that in primary breast cancer (PBC), the transcriptomic expression of ICs including PD-1, CTLA-4, LAG-3 and TIM-3 was significantly higher in tumor tissue (TT) compared with normal tissue (NT). 12 Additionally, in CRC patients, ICs including PD-1, CTLA-4, TIM-3 and TIGIT and IC ligands including PD-L1 and galectin-9 were significantly upregulated in TT compared with NT. 13 Besides that, the promoter regions of PD-1, CTLA-4 and TIM-3 in PBC patients 12 and CTLA-4 and TIGIT in CRC patients, were significantly hypomethylated in TT, compared with NT.…”

Section: Introductionmentioning

confidence: 89%

“…12 Additionally, in CRC patients, ICs including PD-1, CTLA-4, TIM-3 and TIGIT and IC ligands including PD-L1 and galectin-9 were significantly upregulated in TT compared with NT. 13 Besides that, the promoter regions of PD-1, CTLA-4 and TIM-3 in PBC patients 12 and CTLA-4 and TIGIT in CRC patients, were significantly hypomethylated in TT, compared with NT. 13 Therefore, to check the molecular mechanism behind the expression of immune checkpoints and ligand in circulation, we investigated the transcriptomic expression analysis of various immune checkpoints/ligand, and also their promoter methylation pattern of both PBC and CRC patients compared to HD and tumor tissue.…”

Section: Introductionmentioning

confidence: 89%

“…We had already reported that the demethylation enzymes (TETs) were upregulated and methylation enzymes (DNMTs) were downregulated in both PBC and CRC tumor tissues. 12,13 To check the contribution of DNA methylation to the upregulation of ICs/ligand in circulation of PBC and CRC patients, we checked the expressions of methylation enzymes, DNMT3a and DNMT3b, and demethylation enzymes TET2 and TET3, compared to HD. We found that DNMT3a was significantly upregulated and no significant change in DNMT3b in PBC samples, compared with HD.…”

Section: Demethylation Enzymes Were Upregulated In Circulation Of Pbcmentioning

confidence: 99%

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DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients

et al. 2018

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Aberrant expression of immune checkpoints (ICs) in cancer creates an immunosuppressive microenvironment, which supports immune evasion of tumor cells. We have recently reported that epigenetic modifications are critical for ICs expression in the tumor microenvironment (TME) of primary breast cancer (PBC) and colorectal cancer (CRC). Herein, we investigated transcriptomic expression of ICs (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT) and PD-L1 in peripheral blood of PBC and CRC patients, compared to healthy donors (HD). We found that expressions of TIM-3, TIGIT, PD-L1 were significantly upregulated, while LAG-3 expression was downregulated in peripheral blood of PBC and CRC patients. Demethylation enzymes TET2 and TET3 were also upregulated. In addition, promoter DNA methylation status of PD-1 was significantly hypermethylated, while PD-L1 was hypomethylated in PBC and CRC patients. Furthermore, TIGIT was significantly hypomethylated only in CRC patients. Remarkably, promoter methylation status of LAG-3, TIGIT and PD-L1 was in concordance with transcriptomic expression in CRC: the more the hypomethylation, the higher the expression. In comparison, we found that CTLA-4, TIM-3, TIGIT and PD-L1 in PBC, and CTLA-4 in CRC patients were significantly upregulated in peripheral blood, compared with tumor tissues of the same patients. However, demethylation status of all ICs was higher in TT, except for TIGIT in PBC, and CTLA-4 in CRC patients. These data indicate that the underlying mechanisms behind peripheral upregulation of PD-L1 and TIGIT in cancer patients could be due to aberrant promoter methylation profile. Moreover, demethylation inhibitors together with anti-PD-L1/ anti-TIGIT could be a more efficient therapeutic strategy in cancer patients. ARTICLE HISTORY

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 89%

Section: Demethylation Enzymes Were Upregulated In Circulation Of Pbcmentioning

confidence: 99%

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DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients

et al. 2018

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“…Alternatively, promoter demethylation and distribution of repressive histones can work together to induce the upregulation of many genes in cancers [80]. Besides, it has been suggested that the enrichment of repressive histones, histone 3 lysine 9 trimethylation (H3K9me3) and H3K27me3 in the promoter regions along with CpG hypermethylation are the common epigenetic modifications in breast cancer [74]. Therefore, we hypothesized that TNFR2 gene might be highly expressed and demethylated in cancer models.…”

Section: Dna Demethylation and Immune Evasionmentioning

confidence: 98%

“…Although the critical role of TNFR2 in immune evasion of tumor cells, no study to date has been investigated on DNA methylation/demethylation in the TNFR2 gene in cancer subjects. Whereas there were significant findings have been reported recently in studies investigated on methylation/demethylation in several immune checkpoint genes including PD-1, PD-L1, CTLA-4, TIM-3, LAG-3 and TIGIT [73,74]. Demethylation and many mechanisms are part of the epigenetics field, which is considered as a gate for promising trends in cancer research in the current era.…”

Section: Dna Demethylation and Immune Evasionmentioning

confidence: 99%

Synergistic Effects of Nanomedicine Targeting TNFR2 and DNA Demethylation Inhibitor—An Opportunity for Cancer Treatment

Al-Hatamleh

Boer

et al. 2019

Cells

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Tumor necrosis factor receptor 2 (TNFR2) is expressed on some tumor cells, such as myeloma, Hodgkin lymphoma, colon cancer and ovarian cancer, as well as immunosuppressive cells. There is increasingly evidence that TNFR2 expression in cancer microenvironment has significant implications in cancer progression, metastasis and immune evasion. Although nanomedicine has been extensively studied as a carrier of cancer immunotherapeutic agents, no study to date has investigated TNFR2-targeting nanomedicine in cancer treatment. From an epigenetic perspective, previous studies indicate that DNA demethylation might be responsible for high expressions of TNFR2 in cancer models. This perspective review discusses a novel therapeutic strategy based on nanomedicine that has the capacity to target TNFR2 along with inhibition of DNA demethylation. This approach may maximize the anti-cancer potential of nanomedicine-based immunotherapy and, consequently, markedly improve the outcomes of the management of patients with malignancy.Cells 2020, 9, 33 2 of 16 and tumor cells [6][7][8]. In contrast, TNFR2 expression was only reported on tumor cells and suppressive immune cells, suggesting that TNFR2 directly promotes cancer development [9]. Furthermore, the latest preclinical and clinical studies confirmed the implication of TNF-TNFR2 signaling in cancer proliferation and the suppression of immune response [10,11]. Consequently, blockade of TNF-TNFR2 axis could be a promising option for cancer treatment (Figure 1).On the other hand, nanotechnology provided several platforms in the field of immunotherapy and made significant advances towards safe and efficient targeting systems with positive clinical outcomes and minimal side effects; this is the so-called field of nanomedicine [12]. Despite the emerging trends of using nanoparticles in immunotherapy, no studies have investigated any type of nanocarriers to target TNFR2 on cancer cells. However, based on some previous novel reports about the effects of nanoparticles on immune homeostasis [13], especially using nanoparticles to promote TNFR2 + Foxp3 + regulatory T cells (Tregs) in inflammatory models [14,15], we have suggested in our recent perspective review the possibility of blocking TNF-TNFR2 axis via nanoparticles [16].

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Epigenetic Drugs as Modulators of Tumor Immunogenicity and Host Immune Response

Marchi,

Pal,

Manvalan

et al. 2024

Precision Cancer Therapies Vol 2 ‐ Immunologic Approaches for the Treatment of Lymphoid Malignancies ‐ From Concept to Practice

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DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer

Cited by 102 publications

References 63 publications

DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients

DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients

Synergistic Effects of Nanomedicine Targeting TNFR2 and DNA Demethylation Inhibitor—An Opportunity for Cancer Treatment

Epigenetic Drugs as Modulators of Tumor Immunogenicity and Host Immune Response

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