Regulation of PD-L1: Emerging Routes for Targeting Tumor Immune Evasion

Wang, Yiting; Wang, Huanbin; Yao, Han; Li, Chushu; Fang, Jing‐Yuan; Xu, Jin-Quan

doi:10.3389/fphar.2018.00536

Cited by 177 publications

(169 citation statements)

References 105 publications

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…Another interesting observation from the current study was the novel finding that SUV exposure led to significant upregulation of Pd‐l1 mRNA in the epidermis. PD‐L1 is a known IFNγ regulated gene that plays a role in suppressing cytotoxic T‐cell function . PD‐L1 binding to its receptor, PD‐1, on the surface of T‐cells leading to eventual T‐cell exhaustion and ineffective T‐cell function .…”

Section: Discussionmentioning

confidence: 99%

“…PD-L1 is a known IFNγ regulated gene that plays a role in suppressing cytotoxic T-cell function. 102 PD-L1 binding to its receptor, PD-1, on the surface of T-cells leading to eventual T-cell exhaustion and ineffective T-cell function. 102 As shown in Figures 3 and 5, SUV-induced Pd-l1 mRNA expression was dependent on functional IFNγ/pSTAT1/IRF-1 signaling in keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

“…102 PD-L1 binding to its receptor, PD-1, on the surface of T-cells leading to eventual T-cell exhaustion and ineffective T-cell function. 102 As shown in Figures 3 and 5, SUV-induced Pd-l1 mRNA expression was dependent on functional IFNγ/pSTAT1/IRF-1 signaling in keratinocytes. UV-induced immune suppression in skin carcinogenesis is a well known phenomenon that has been widely studied and involves a number of alterations.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Activation of a protumorigenic IFNγ/STAT1/IRF‐1 signaling pathway in keratinocytes following exposure to solar ultraviolet light

Blazanin

Cheng

Carbajal

et al. 2019

Molecular Carcinogenesis

View full text Add to dashboard Cite

In this study, we evaluated the role of signal transducer and activator of transcription 1 (STAT1) in response to acute solar ultraviolet (SUV) radiation in mouse epidermis. Analysis of the epidermis from SUV‐irradiated mice revealed rapid phosphorylation of STAT1 (pSTAT1) on both tyrosine (tyr701) and serine (ser727) residues and increased levels of IRF‐1 while later timepoints showed increased levels of unphosphorylated STAT1 (uSTAT1). STAT1 activation led to upregulation of several proinflammatory chemokine mRNAs in epidermis including Cxcl9, Cxcl10, and Ccl2, as well as, the immune checkpoint inhibitor Pd‐l1. In addition, mRNA and protein levels of cyclooxygenase‐2 (Cox‐2/COX2) were upregulated in epidermis following exposure to SUV. Mice with keratinocyte‐specific STAT1 deletion did not exhibit increased IRF‐1 or proinflammatory gene expression in epidermis. Furthermore, epidermal COX‐2 induction after SUV exposure was significantly reduced in mice with keratinocyte‐specific deletion of STAT1. Additionally, SUV irradiation rapidly upregulated interferon gamma (IFNγ) mRNA in the epidermis and that skin resident epidermal CD3 + T‐cells were the source of IFNγ production. IFNγ receptor‐deficient mice confirmed dependency of STAT1 activation, proinflammatory gene expression and COX‐2 upregulation in the epidermis on paracrine IFNγ signaling. Furthermore, keratinocyte‐specific STAT1‐deficiency reduced proliferation and hyperplasia due to SUV irradiation and this was associated with decreased immune infiltration of mast cells in the dermis. Collectively, the current results demonstrate that exposure to SUV leads to upregulation of IFNγ and downstream pSTAT1/IRF‐1/uSTAT1 signaling in the epidermis. Further study of this pathway could lead to identification of novel targets for the prevention of nonmelanoma skin cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Activation of a protumorigenic IFNγ/STAT1/IRF‐1 signaling pathway in keratinocytes following exposure to solar ultraviolet light

Blazanin

Cheng

Carbajal

et al. 2019

Molecular Carcinogenesis

View full text Add to dashboard Cite

show abstract

“…There is long‐standing evidence that EBV core proteins, such as EBNA2, upregulate PD‐L1 to evade immune surveillance. However, in the context of lymphomagenesis various non‐genetic factors such as miR‐34 and others, seem to influence PD‐L1 expression, as well . In our study, apart from 3 of 29 PTLD samples analyzed, all showed EBV positivity on all tested occasions.…”

Section: Discussionmentioning

confidence: 99%

PD‐L1 and PD1 expression in post‐transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: An inter‐ and intra‐individual descriptive study covering the whole spectrum of PTLD categories

et al. 2019

View full text Add to dashboard Cite

Therapy of children with post‐transplantation lymphoproliferative disorder (PTLD) after hematopoietic stem cell (HSCT) and solid organ transplantation (SOT) can be challenging. In this retrospective study, we investigated PD‐L1 and PD1 expression in all PTLD categories of childhood and adolescence to see whether checkpoint inhibition with PD‐L1/PD1 inhibitors may serve as a therapy option. We included 21 patients aged 19 years or younger (at date of transplant) with PTLD following SOT or HSCT having adequate tumor samples available (n = 29). Using immunohistochemistry, we evaluated PD‐L1/PD1 expression on both tumor cells and cells of the microenvironment in all samples. Availability of consecutively matched tumor samples during 6 of 21 patients' disease courses also allowed an intra‐individual assessment of PD‐L1/PD1 expression. We observed lower PD‐L1 and higher PD1 expression in non‐destructive lesions, and higher PD‐L1 and lower PD1 expression in polymorphic and, in particular, in monomorphic PTLD, mostly diffuse large B‐cell lymphomas (DLBCL, n = 10/21). The amount of PD‐L1‐ and PD1‐positive cells changed in the opposite way in sequential biopsies of the same individual correlating well with the PTLD category. This is the first comprehensive pediatric study assessing PD‐L1 and PD1 expression on tumor cells and in the microenvironment of PTLD including not only monomorphic, but also non‐destructive early lesions. PD‐L1 expression of the tumor cells inversely correlated with PD1 expression in surrounding tissues, with the highest expression in DLBCL. Since PTLD can be therapeutically challenging, our results indicate a potential efficacy of checkpoint inhibitors if standard immune‐ and/or chemotherapy fail or are impossible. We therefore recommend routine staining of PD‐L1 and PD1 in all PTLD categories.

show abstract

“…Recently, programmed death‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) checkpoint blockades have gradually become an effective therapeutic strategy for several types of tumors 6 . Immunotherapeutic strategies inhibiting the PD‐L1/PD‐1 axis have been applied to the treatment of glioma and better clinical efficacies of PD‐1/PD‐L1 checkpoint blockades have been demonstrated 7,8 . However, the relationship between high PD‐L1 expression and clinical prognosis in GBM remains controversial 9 .…”

Section: Introductionmentioning

confidence: 99%

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

Guo

Lou

et al. 2020

Molecular Carcinogenesis

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most common and malignant brain tumor in adults. Recently, programmed death‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) checkpoint blockades have been applied for GBM treatment. However, the mechanism of PD‐L1 upregulation in GBM is still unclear. COP9 signalosome 6 (CSN6) is crucial for maintaining the protein stabilization in cancer cells. In this study, we applied human GBM specimens and cell lines to investigate whether the EGFR‐ERK pathway regulates CSN6 for PD‐L1 upregulation. Data from The Cancer Genome Atlas dataset showed that high expression of EGFR, CSN6, and PD‐L1 in patients with glioma was associated with poor prognosis. In 47 human GBM specimens, high expression of PD‐L1 was associated with low amount of CD8+ T cell infiltration as well as the poor prognosis of patients. CSN6 was positively correlated with EGFR and PD‐L1 expression in human GBM specimens. We treated two GBM cell lines (U87 and U251) with epidermal growth factor (EGF) in vitro, and found EGF‐upregulated p‐EGFR, p‐ERK, CSN6, and PD‐L1 expression in GBM cells. PD98059, the ERK blocker, inhibited upregulations of CSN6 and PD‐L1 in EGF‐treated cells. Inhibition of CSN6 by small interfering RNA decreased PD‐L1 expression but also increased CHIP expression in GBM cells. When the cells were treated with EGF and cycloheximide (CHX), a protein synthesis inhibitor, EGF‐reduced CHX‐induced CSN6 and PD‐L1 turnover in GBM cells. Furthermore, CSN6‐mediated downregulation of PD‐L1 was inhibited by MG132, a proteasome inhibitor in U87 cells. Thus, these results suggest that the EGFR‐ERK pathway may upregulate CSN6, which may inhibit PD‐L1 degradation and subsequently maintain PD‐L1 stability in GBM.

show abstract

Regulation of PD-L1: Emerging Routes for Targeting Tumor Immune Evasion

Cited by 177 publications

References 105 publications

Activation of a protumorigenic IFNγ/STAT1/IRF‐1 signaling pathway in keratinocytes following exposure to solar ultraviolet light

Activation of a protumorigenic IFNγ/STAT1/IRF‐1 signaling pathway in keratinocytes following exposure to solar ultraviolet light

PD‐L1 and PD1 expression in post‐transplantation lymphoproliferative disease (PTLD) of childhood and adolescence: An inter‐ and intra‐individual descriptive study covering the whole spectrum of PTLD categories

EGFR‐ERK pathway regulates CSN6 to contribute to PD‐L1 expression in glioblastoma

Contact Info

Product

Resources

About