Interferon regulatory factor 1 (IRF-1) and IRF-2 regulate PD-L1 expression in hepatocellular carcinoma (HCC) cells

Yan, Yaohua; Zheng, Leting; Du, Qiang; Yan, Bing; Geller, David A.

doi:10.1007/s00262-020-02586-9

Cited by 68 publications

(50 citation statements)

References 40 publications

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“…IRF-1 is the vital downstream component of STAT1 upon IFN-γ treatment [46,47]. In hepatocellular carcinoma, it was identified that two elements (IRE1/2) in the 5′-flanking region of the CD274 promoter were the binding sites of IRF-1, which participated in regulating PD-L1 transcription [48]. Notably, the intactness of JAK-STAT-IRF1 pathway is also related to the response to α-PD-1/PD-L1 therapy.…”

Section: Inflammatory Signaling Interferon (Ifn) and Il-6mentioning

confidence: 99%

Regulation of PD-L1 expression in the tumor microenvironment

et al. 2021

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Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.

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Section: Inflammatory Signaling Interferon (Ifn) and Il-6mentioning

confidence: 99%

Regulation of PD-L1 expression in the tumor microenvironment

et al. 2021

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“…The presence of tumor suppressor TET2 mediates PD-L1 expression via the IFN--JAK2-STAT1 axis (28). In contrast, loss of tumor suppressor IRF-1 is associated with PD-L1 downregulation caused by loss of its antagonistic activity against IRF-2, a transcription repressor of PD-L1 (29,30). Similarly, loss of the tumor suppressor cyclin-dependent kinase 5 (CDK5) diminishes PD-L1 expression via promoting expression of PD-L1 repressors, including IRF-2 and IRF2BP2 (31).…”

Section: Aberrant Oncogenic Signaling Pathwaysmentioning

confidence: 99%

Current understanding of cancer-intrinsic PD-L1: regulation of expression and its protumoral activity

Yadollahi

Jeon

et al. 2021

BMB Rep.

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In the last decade, we have witnessed an unprecedented clinical success in cancer immunotherapies targeting the programmed cell-death ligand 1 (PD-L1) and programmed cell-death 1 (PD-1) pathway. Besides the fact that PD-L1 plays a key role in immune regulation in tumor microenvironment, recently a plethora of reports has suggested a new perspective of non-immunological functions of PD-L1 in the regulation of cancer intrinsic activities including mesenchymal transition, glucose and lipid metabolism, stemness, and autophagy. Here we review the current understanding on the regulation of expression and intrinsic protumoral activity of cancer-intrinsic PD-L1.

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“…Nonetheless, the putative master regulators of ICs, as listed in Table 1, may serve as a good starting point to elucidate their potential as suitable therapeutic targets. Simultaneously, efforts should be made to identify more master regulators of ICs for fruitful results [67], pancreatic cancer [68], and melanoma [69]. This transcription factor functions by binding to the flanking region of the PD-L1 promoter.…”

Section: Known Putative Master Regulators Of Icsmentioning

confidence: 99%

“…This transcription factor functions by binding to the flanking region of the PD-L1 promoter. Conversely, IRF2 downregulates this transcriptional activation by binding to the response elements [67]. IRF1 has been shown to communicate with other transcription factors, including STAT1 and BRD4 [68], which affects the regulation of PD-L1.…”

Section: Known Putative Master Regulators Of Icsmentioning

confidence: 99%

Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

et al. 2020

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The study of immune evasion has gained a well-deserved eminence in cancer research by successfully developing a new class of therapeutics, immune checkpoint inhibitors, such as pembrolizumab and nivolumab, anti-PD-1 antibodies. By aiming at the immune checkpoint blockade (ICB), these new therapeutics have advanced cancer treatment with notable increases in overall survival and tumor remission. However, recent reports reveal that 40–60% of patients fail to benefit from ICB therapy due to acquired resistance or tumor relapse. This resistance may stem from increased expression of co-inhibitory immune checkpoints or alterations in the tumor microenvironment that promotes immune suppression. Because these mechanisms are poorly elucidated, the transcription factors that regulate immune checkpoints, known as “master regulators”, have garnered interest. These include AP-1, IRF-1, MYC, and STAT3, which are known to regulate PD/PD-L1 and CTLA-4. Identifying these and other potential master regulators as putative therapeutic targets or biomarkers can be facilitated by mining cancer literature, public datasets, and cancer genomics resources. In this review, we describe recent advances in master regulator identification and characterization of the mechanisms underlying immune checkpoints regulation, and discuss how these master regulators of immune checkpoint molecular expression can be targeted as a form of auxiliary therapeutic strategy to complement traditional immunotherapy.

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Interferon regulatory factor 1 (IRF-1) and IRF-2 regulate PD-L1 expression in hepatocellular carcinoma (HCC) cells

Cited by 68 publications

References 40 publications

Regulation of PD-L1 expression in the tumor microenvironment

Regulation of PD-L1 expression in the tumor microenvironment

Current understanding of cancer-intrinsic PD-L1: regulation of expression and its protumoral activity

Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

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