Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression

García-Díaz, Ángel; Shin, Daniel Sanghoon; Moreno, Blanca Homet; Saco, Justin D.; Escuin-Ordinas, Helena; Rodriguez, Gabriel Abril; Zaretsky, Jesse M.; Sun, Lei; Hugo, Willy; Wang, Xiaoyan; Parisi, Giulia; Puig-Saus, Cristina; Torrejon, Davis Y.; Graeber, Thomas G.; Comin-Anduix, Begoñya; Hu‐Lieskovan, Siwen; Damoiseaux, Robert; Lo, Roger S.; Ribas, Antoni

doi:10.1016/j.celrep.2019.11.113

Cited by 308 publications

(415 citation statements)

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“…3 Generally, in the context of the immune response, PD-L1 expression is controlled by STAT1/3 phosphorylation and IRF1 expression following the stimulation of IFNγ. 20,21 Interferon regulatory factor 1 binds to the promoter region of PD-L1 to upregulate PD-L1 transcription. 21 Interestingly, we found that phosphorylation of STAT1/3 as well as IRF1 expression are induced by DNA damage.…”

Section: Reg Ul Ati On Of Pd -Le Xpre Ss I On In Re S P On S E To Dmentioning

confidence: 99%

Regulation of programmed death‐ligand 1 expression in response to DNA damage in cancer cells: Implications for precision medicine

2019

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Anti‐programmed death‐1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) therapy, which is one of the most promising cancer therapies, is licensed for treating various tumors. Programmed death‐ligand 1, which is expressed on the surface of cancer cells, leads to the inhibition of T lymphocyte activation and immune evasion if it binds to the receptor PD‐1 on CTLs. Anti‐PD‐1/PD‐L1 Abs inhibit interactions between PD‐1 and PD‐L1 to restore antitumor immunity. Although certain patients achieve effective responses to anti‐PD‐1/PD‐L1 therapy, the efficacy of treatment is highly variable. Clinical trials of anti‐PD‐1/PD‐L1 therapy combined with radiotherapy/chemotherapy are underway with suggestive evidence of favorable outcome; however, the molecular mechanism is largely unknown. Among several molecular targets that can influence the efficacy of anti‐PD‐1/PD‐L1 therapy, PD‐L1 expression in tumors is considered to be a critical biomarker because there is a positive correlation between the efficacy of combined treatment protocols and PD‐L1 expression levels. Therefore, understanding the mechanisms underlying the regulation of PD‐L1 expression in cancer cells, particularly the mechanism of PD‐L1 expression following DNA damage, is important. In this review, we consider recent findings on the regulation of PD‐L1 expression in response to DNA damage signaling in cancer cells.

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Section: Reg Ul Ati On Of Pd -Le Xpre Ss I On In Re S P On S E To Dmentioning

confidence: 99%

Regulation of programmed death‐ligand 1 expression in response to DNA damage in cancer cells: Implications for precision medicine

2019

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“…Reportedly, STAT2 is one of the mediators to promote PD-L1 transcription. 5 Additionally, STAT3 plays an important transcriptional role of PD-L1, 31 and c-JUN has been reported to promote its transcription by acting together with STAT3. 8 However, S-727 phosphorylation of STAT3 has been reported to have an intrinsic mechanism for shortening the duration of STAT3 activity, 32 hence S-727 phosphorylation is expected to regulate PD-L1 expression negatively.…”

Section: Discussionmentioning

confidence: 99%

“…and PD-L1 constitute a key pathway in local tumor immunosuppression, and inhibition of the PD-1-PD-L1 axis has been reported to be an effective therapy for various malignancies. [3][4][5][6] Expression of PD-L1 in tumor cells is regulated by several extrinsic and intrinsic factors. 7,8 In particular, γ-interferon (IFN-γ) in the tumor microenvironment has been reported to be a key extrinsic regulator of PD-L1 expression.…”

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confidence: 99%

“…IFN-γ principally activates JAK and STAT signaling pathways, which induce the direct binding of its transcription factor, IFN regulatory factor 1, to the promoter region of PD-L1. [3][4][5]9 However, expression of PD-L1 by IFN-γ stimulation is mediated by multiple mechanisms. In medulloblastomas, IFN-γ induces PD-L1 upregulation, which is required for the supportive effect of cyclin-dependent kinase 5.…”

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confidence: 99%

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Macrophage migration inhibitory factor‐CD74 interaction regulates the expression of programmed cell death ligand 1 in melanoma cells

et al. 2019

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Expression of programmed cell death ligand 1 (PD‐L1) on tumor cells contributes to cancer immune evasion by interacting with programmed cell death 1 on immune cells. γ‐Interferon (IFN‐γ) has been reported as a key extrinsic stimulator of PD‐L1 expression, yet its mechanism of expression is poorly understood. This study analyzed the role of CD74 and its ligand macrophage migration inhibitory factor (MIF) on PD‐L1 expression, by immunohistochemical analysis of melanoma tissue samples and in vitro analyses of melanoma cell lines treated with IFN‐γ and inhibitors of the MIF‐CD74 interaction. Immunohistochemical analyses of 97 melanoma tissue samples showed significant correlations between CD74 and the expression status of PD‐L1 (P < .01). In vitro analysis of 2 melanoma cell lines, which are known to secrete MIF constitutively and express cell surface CD74 following IFN‐γ stimulation, showed upregulation of PD‐L1 levels by IFN‐γ stimulation. This was suppressed by further treatment with the MIF‐CD74 interaction inhibitor, 4‐iodo‐6‐phenylpyrimidine. In the analysis of melanoma cell line WM1361A, which constitutively expresses PD‐L1, CD74, and MIF in its non‐treated state, treatment with 4‐iodo‐6‐phenylpyrimidine and transfection of siRNAs targeting MIF and CD74 significantly suppressed the expression of PD‐L1. Together, the results indicated that MIF‐CD74 interaction directly regulated the expression of PD‐L1 and helps tumor cells escape from antitumorigenic immune responses. In conclusion, the MIF‐CD74 interaction could be a therapeutic target in the treatment of melanoma patients.

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“…However, similar to overexuberant innate responses, unchecked CD8 T cell responses can lead to extensive tissue damage. The IFNa/b response thus also comprises negative regulators, such as suppressors of cytokine signaling (SOCSs), or PD-L1 and PD-L2 that downregulate ongoing activation and control excessive T cell function (15,31,36 Aside from numerous studies on individual IFNARmediated functions, the impact of IFNa/b on the global antiviral program was demonstrated using a model of CNS infection by lymphocytic choriomeningitis virus (LCMV), a noncytopathic arenavirus (27). Although intracranial infection by LCMV causes a fatal meningitis due to effector functions of infiltrating cytotoxic T lymphocytes and myeloid cells, it establishes asymptomatic long-term persistence in mice with a highly restricted CD8 T cell repertoire specific for ovalbumin (OT-I mice).…”

Section: Introductionmentioning

confidence: 99%

Intercellular Communication Is Key for Protective IFNα/β Signaling During Viral Central Nervous System Infection

Hwang

Bergmann

2019

Viral Immunology

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A variety of viruses can induce central nervous system (CNS) infections and neurological diseases, although the incidence is rare. Similar to peripheral infections, IFNα/β induction and signaling constitutes a first line of defense to limit virus dissemination. However, CNS-resident cells differ widely in their repertoire and magnitude of both basal and inducible components in the IFNα/β pathway. While microglia as resident myeloid cells have been implicated as prominent sentinels of CNS invading pathogens or insults, astrocytes are emerging as key responders to many neurotropic RNA virus infections. Focusing on RNA viruses, this review discusses the role of astrocytes as IFNα/β inducers and responders and touches on the role of IFNα/β receptor signaling in regulating myeloid cell activation and IFNγ responsiveness. A summary picture emerges implicating IFNα/β not only as key in establishing the classical "antiviral" state, but also orchestrating cell mobility and IFNγ-mediated effector functions.

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Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression

Abstract: In the originally published version of this article, the PD-L1 promoter was mistakenly described to be cloned into the BglII/SacI sites of the pGL3 basic vector instead of the BglII site.

Cited by 308 publications

References 0 publications

Regulation of programmed death‐ligand 1 expression in response to DNA damage in cancer cells: Implications for precision medicine

Regulation of programmed death‐ligand 1 expression in response to DNA damage in cancer cells: Implications for precision medicine

Macrophage migration inhibitory factor‐CD74 interaction regulates the expression of programmed cell death ligand 1 in melanoma cells

Intercellular Communication Is Key for Protective IFNα/β Signaling During Viral Central Nervous System Infection

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