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

Ma, Xiaoran; Wu, Jibiao; Wang, Bin; Liu, Cun; Liu, Lijuan; Sun, Changgang

doi:10.3892/ijo.2022.5424

Cited by 6 publications

(5 citation statements)

References 186 publications

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“…Moreover, genetic/epigenetic alterations could affect PD-L1 expression as well. For example, in squamous cell NSCLC elevated levels of histone deacetylases (HDAC), such as HDAC3 and HDAC6, are detected, that are reported to upregulate PD-L1 expression by STAT3 signalling pathway in melanoma, osteosarcoma, and pancreatic cancer [ 77 , 78 ]. Furthermore, PD-L1 expression in dendritic cells in the TME and PD-L1 transcription in tumour cells are elevated through increased interferon -γ (IFN-γ) production and acetylation of PD-L1 promoter region histone after HDAC3 expression inhibition [ 78 ].…”

Section: Discussionmentioning

confidence: 99%

PD-L1 Expression and Tumour Microenvironment Patterns in Resected Non-Small-Cell Lung Cancer

Gurevičienė,

Matulionė,

Poškienė

et al. 2024

Medicina

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Background and Objectives: Although perioperative immunotherapy is implemented as a standard of care for resected non-small cell lung cancer (NSCLC), there is unmet need for predictive biomarkers as programmed death-ligand 1 (PD-L1) is not the perfect one. The functionality of tumour-infiltrating immune cells in the tumour microenvironment (TME) and the involvement in immune system response is one of the crucial factors that lead to pro- or anti-tumourigenic role and could predict response to PD-1 and PD-L1 inhibitors. So, the investigation of PD-L1 expression in the context of TME in early stages of resected NSCLC is urgent required. Materials and Methods: PD-L1 expression by three scoring methods: tumour proportion score (TPS), immune cell score (IC), and combined proportion score (CPS) was assessed in 72 archival tumour tissue specimens from stage I–III surgically resected NSCLC patients and associations with immune cells in TME were explored. Results: PD-L1 expression ≥1% evaluated by TPS, IC, and CPS was detected in 28%, 36%, and 39% of cases and moderate, substantial, and strong agreement between TPS and IC, TPS and CPS, CPS and IC was detected (Cohen’s κ coefficient 0.556, 0.63, and 0.941, respectively). PD-L1 TPS, IC, and CPS correlated with smoking intensity defined as pack-years (r = 0.0305, p = 0.012; r = 0.305, p = 0.013, and r = 0.378, p = 0.002, respectively). Only PD-L1 TPS was associated with squamous cell carcinoma (p = 0.028). PD-L1 IC ≥1% was more often seen in tumours with high CD4+ T cells infiltration (p = 0.02), while PD-L1 CPS ≥1%—in tumours with high CD4+ and CD8+ T cells infiltration (p = 0.021 and p = 0.048, respectively). PD-L1 IC and CPS ≥10% was more often detected in tumours with greater number of tumour-infiltrating CD4+Foxp3+ T cells (p = 0.01 and p = 0.025, respectively). PD-L1 TPS ≥50% was associated with higher probability to detect greater number of tumour-infiltrating M2 macrophages (p = 0.021). No association was found between PD-L1 alone or in combination with tumour-infiltrating lymphocytes, macrophages, and disease-free or overall survival. Conclusions: This study results revealed that rates of PD-L1 expression correlated among three scoring methods (TPS, IC, and CPS). Moreover, PD-L1 expression was significantly associated with smoking intensity, squamous histology, and tumour-infiltrating immune cells.

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Section: Discussionmentioning

confidence: 99%

PD-L1 Expression and Tumour Microenvironment Patterns in Resected Non-Small-Cell Lung Cancer

Gurevičienė,

Matulionė,

Poškienė

et al. 2024

Medicina

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“…The regulation of histone acetylation and deacetylation is another epigenetic mechanism which regulates the transcription of the PD-L1 gene and thus it is an important therapeutic target [ 96 ]. The acetylation of histones facilitates the opening of chromatin and consequently enhances the transcription of genes.…”

Section: The Aging-associated Signaling Stimulates the Expression Of ...mentioning

confidence: 99%

The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

Salminen

2024

J Mol Med

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The accumulation of senescent cells within tissues is a hallmark of the aging process. Senescent cells are also commonly present in many age-related diseases and in the cancer microenvironment. The escape of abnormal cells from immune surveillance indicates that there is some defect in the function of cytotoxic immune cells, e.g., CD8+ T cells and natural killer (NK) cells. Recent studies have revealed that the expression of programmed death-ligand 1 (PD-L1) protein is abundantly increased in senescent cells. An increase in the amount of PD-L1 protein protects senescent cells from clearance by the PD-1 checkpoint receptor in cytotoxic immune cells. In fact, the activation of the PD-1 receptor suppresses the cytotoxic properties of CD8+ T and NK cells, promoting a state of immunosenescence. The inhibitory PD-1/PD-L1 checkpoint pathway acts in cooperation with immunosuppressive cells; for example, activation of PD-1 receptor can enhance the differentiation of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and M2 macrophages, whereas the cytokines secreted by immunosuppressive cells stimulate the expression of the immunosuppressive PD-L1 protein. Interestingly, many signaling pathways known to promote cellular senescence and the aging process are crucial stimulators of the expression of PD-L1 protein, e.g., epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, and AhR signaling. It seems that the inhibitory PD-1/PD-L1 immune checkpoint axis has a crucial role in the accumulation of senescent cells and thus it promotes the aging process in tissues. Thus, the blockade of the PD-1/PD-L1 checkpoint signaling might be a potential anti-aging senolytic therapy. Key messages Senescent cells accumulate within tissues during aging and age-related diseases. Senescent cells are able to escape immune surveillance by cytotoxic immune cells. Expression of programmed death-ligand 1 (PD-L1) markedly increases in senescent cells. Age-related signaling stimulates the expression of PD-L1 protein in senescent cells. Inhibitory PD-1/PD-L1 checkpoint pathway suppresses clearance of senescent cells.

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“…Moreover, PD-L1 promotes the activation of β-catenin and β-catenin CSC-associated target genes via an interaction with the receptor, Frizzled 6 48 . The expression and stability of PD-L1 is regulated in an epigenetic and posttranslational manner, respectively 51 , 54 , 58 , 59 ; however, the expression landscape of immunomodulatory molecules varies between cancer types and individuals. The underlying regulatory mechanisms are also sophisticated and heterogeneous.…”

Section: Biological Properties Of Cscsmentioning

confidence: 99%

Cancer stem cells: a target for overcoming therapeutic resistance and relapse

Zhang,

Yang,

Ouyang

et al. 2024

Cancer Biol Med

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Cancer stem cells (CSCs) are a small subset of cells in cancers that are thought to initiate tumorous transformation and promote metastasis, recurrence, and resistance to treatment. Growing evidence has revealed the existence of CSCs in various types of cancers and suggested that CSCs differentiate into diverse lineage cells that contribute to tumor progression. We may be able to overcome the limitations of cancer treatment with a comprehensive understanding of the biological features and mechanisms underlying therapeutic resistance in CSCs. This review provides an overview of the properties, biomarkers, and mechanisms of resistance shown by CSCs. Recent findings on metabolic features, especially fatty acid metabolism and ferroptosis in CSCs, are highlighted, along with promising targeting strategies. Targeting CSCs is a potential treatment plan to conquer cancer and prevent resistance and relapse in cancer treatment.

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

Cited by 6 publications

References 186 publications

PD-L1 Expression and Tumour Microenvironment Patterns in Resected Non-Small-Cell Lung Cancer

PD-L1 Expression and Tumour Microenvironment Patterns in Resected Non-Small-Cell Lung Cancer

The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

Cancer stem cells: a target for overcoming therapeutic resistance and relapse

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