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Special Issue "PD-L1, A Master Regulator of Immunity"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 July 2019).

Special Issue Editors

Prof. Karine Breckpot
Website
Guest Editor
Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, Belgium
Dr. David Escors
Website
Guest Editor
Navarrabiomed‐Fundación Miguel Servet, Complejo Hospitalario de Navarra, Pamplona, Spain

Special Issue Information

Dear Colleagues,

Receptor programmed cell death-1 (PD-1) is a co-inhibitory receptor that is mainly expressed on activated T cells. Through binding with its ligand, programmed death ligand-1 (PD-L1), PD-1 regulates the activity of T cells. As such, adaptive immune responses mediated by T cells against invading pathogens are strictly regulated, thereby avoiding collateral damage to the host. This regulatory circuit is however abused in several diseases such as chronic infection and cancer to dampen immune responses prematurely. Blocking the PD-1:PD-L1 immune checkpoint axis has therefore garnered substantial interest. In cancer, PD-1:PD-L1 blockade has resulted in unprecedented successes in individual patients across a variety of cancer types. However, a large cohort of patients fails to respond to PD-1:PD-L1 blockade. Insights into different mechanisms underlying this therapy failure are gradually gained. These highlight the complexity of the immune system and cancer as a disease. They further shed light on how combination with other therapies could enhance the response rates to PD-1:PD-L1 blockade.

Prof. Karine Breckpot
Dr. David Escors
Guest Editors

Manuscript Submission Information

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Keywords

  • PD-1
  • PD-L1
  • T cell
  • Immune checkpoint
  • Myeloid cell
  • Biomarker
  • Cancer
  • Auto-immunity
  • Infectious disease

Published Papers (12 papers)

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Research

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Open AccessArticle
High PD-L1 Expression Predicts for Worse Outcome of Leukemia Patients with Concomitant NPM1 and FLT3 Mutations
Int. J. Mol. Sci. 2019, 20(11), 2823; https://doi.org/10.3390/ijms20112823 - 10 Jun 2019
Cited by 5
Abstract
Compared to solid tumors, the role of PD-L1 in hematological malignancies is less explored, and the knowledge in this area is mostly limited to lymphomas. However, several studies indicated that PD-L1 is also overexpressed in myeloid malignancies. Successful treatment of the acute myeloid [...] Read more.
Compared to solid tumors, the role of PD-L1 in hematological malignancies is less explored, and the knowledge in this area is mostly limited to lymphomas. However, several studies indicated that PD-L1 is also overexpressed in myeloid malignancies. Successful treatment of the acute myeloid leukemia (AML) is likely associated with elimination of the residual disease by the immune system, and possible involvement of PD-L1 in this process remains to be elucidated. We analyzed PD-L1 expression on AML primary cells by flow cytometry and, in parallel, transcript levels were determined for the transcription variants v1 and v2. The ratio of v1/v2 cDNA correlated with the surface protein amount, and high v1/v2 levels were associated with worse overall survival (p = 0.0045). The prognostic impact of PD-L1 was limited to AML with mutated nucleophosmin and concomitant internal tandem duplications in the FLT3 gene (p less than 0.0001 for this particular AML subgroup). Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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Open AccessArticle
PD-L1 Expression in Systemic Immune Cell Populations as a Potential Predictive Biomarker of Responses to PD-L1/PD-1 Blockade Therapy in Lung Cancer
Int. J. Mol. Sci. 2019, 20(7), 1631; https://doi.org/10.3390/ijms20071631 - 02 Apr 2019
Cited by 15
Abstract
PD-L1 tumor expression is a widely used biomarker for patient stratification in PD-L1/PD-1 blockade anticancer therapies, particularly for lung cancer. However, the reliability of this marker is still under debate. Moreover, PD-L1 is widely expressed by many immune cell types, and little is [...] Read more.
PD-L1 tumor expression is a widely used biomarker for patient stratification in PD-L1/PD-1 blockade anticancer therapies, particularly for lung cancer. However, the reliability of this marker is still under debate. Moreover, PD-L1 is widely expressed by many immune cell types, and little is known on the relevance of systemic PD-L1+ cells for responses to immune checkpoint blockade. We present two clinical cases of patients with non-small cell lung cancer (NSCLC) and PD-L1-negative tumors treated with atezolizumab that showed either objective responses or progression. These patients showed major differences in the distribution of PD-L1 expression within systemic immune cells. Based on these results, an exploratory study was carried out with 32 cases of NSCLC patients undergoing PD-L1/PD-1 blockade therapies, to compare PD-L1 expression profiles and their relationships with clinical outcomes. Significant differences in the percentage of PD-L1+ CD11b+ myeloid cell populations were found between objective responders and non-responders. Patients with percentages of PD-L1+ CD11b+ cells above 30% before the start of immunotherapy showed response rates of 50%, and 70% when combined with memory CD4 T cell profiling. These findings indicate that quantification of systemic PD-L1+ myeloid cell subsets could provide a simple biomarker for patient stratification, even if biopsies are scored as PD-L1 null. Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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Open AccessArticle
Role of PD-L1 Expression in Non-Small Cell Lung Cancer and Their Prognostic Significance according to Clinicopathological Factors and Diagnostic Markers
Int. J. Mol. Sci. 2019, 20(4), 824; https://doi.org/10.3390/ijms20040824 - 14 Feb 2019
Cited by 18
Abstract
Background: The latest immunotherapy, used in the treatment of non-small cell lung cancer (NSCLC), uses monoclonal antibodies directed against programmed death ligand 1 (PD-L1) to inhibit its interaction with the PD-1 receptor. Elevated levels of PD-L1 expression were observed on NSCLC cells. The [...] Read more.
Background: The latest immunotherapy, used in the treatment of non-small cell lung cancer (NSCLC), uses monoclonal antibodies directed against programmed death ligand 1 (PD-L1) to inhibit its interaction with the PD-1 receptor. Elevated levels of PD-L1 expression were observed on NSCLC cells. The association between PD-L1 expression and clinicopathological features is still unclear. Therefore, we examined this relationship and also compare PD-L1 expression levels with Ki-67, p63 and TTF-1. Methods: 866 samples of NSCLCs were used to prepare tissue microarrays (TMAs) on which immunohistochemical (IHC) reactions were performed. Changes in the level of CD274 (PD-L1) gene expression in 62 NSCLC tumors were tested in relation to 14 normal lung tissues by real-time PCR reactions (RT-PCR). Results: PD-L1 expression was observed in 32.6% of NSCLCs. PD-L1 expression was increased in higher malignancy grades (G) (p < 0.0001) and in higher lymph node status (pN) (p = 0.0428). The patients with low PD-L1 expression had longer overall survival compared to the group with high expression (p = 0.0332) in adenocarcinoma (AC) only. Conclusions: PD-L1 expression seems to be associated with increased tumor proliferation and aggressiveness as well as shorter patient survival in NSCLC, predominantly in the AC group. Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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Review

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Open AccessReview
Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC)
Int. J. Mol. Sci. 2019, 20(15), 3821; https://doi.org/10.3390/ijms20153821 - 05 Aug 2019
Cited by 15
Abstract
The epidermal growth factor receptor (EGFR) pathway is a well-studied oncogenic pathway in human non-small cell lung cancer (NSCLC). A subset of advanced NSCLC patients (15–55%) have EGFR-driven mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) targeting [...] Read more.
The epidermal growth factor receptor (EGFR) pathway is a well-studied oncogenic pathway in human non-small cell lung cancer (NSCLC). A subset of advanced NSCLC patients (15–55%) have EGFR-driven mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) targeting the PD-1/PDL-1 axis are a new anti-cancer therapy for metastatic NSCLC. The anti-PD-1/PDL-1 ICIs showed promising efficacy (~30% response rate) and improved the survival of patients with metastatic NSCLC, but the role of anti-PD-1/PDL-1 ICIs for EGFR mutant NSCLC is not clear. YAP (yes-associated protein) is the main mediator of the Hippo pathway and has been identified as promoting cancer progression, drug resistance, and metastasis in NSCLC. Here, we review recent studies that examined the correlation between the EGFR, YAP pathways, and PD-L1 and demonstrate the mechanism by which EGFR and YAP regulate PD-L1 expression in human NSCLC. About 50% of EGFR mutant NSCLC patients acquire resistance to EGFR-TKIs without known targetable secondary mutations. Targeting YAP therapy is suggested as a potential treatment for NSCLC with acquired resistance to EGFR-TKIs. Future work should focus on the efficacy of YAP inhibitors in combination with immune checkpoint PD-L1/PD-1 blockade in EGFR mutant NSCLC without targetable resistant mutations. Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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Open AccessReview
Programmed Cell Death-1 Receptor (PD-1)-Mediated Regulation of Innate Lymphoid Cells
Int. J. Mol. Sci. 2019, 20(11), 2836; https://doi.org/10.3390/ijms20112836 - 11 Jun 2019
Cited by 5
Abstract
Programmed cell death-1 (PD-1) is a cell surface receptor that dampens adaptive immune responses. PD-1 is activated by the engagement of its ligands PDL-1 or PDL-2. This results in the inhibition of T cell proliferation, differentiation, cytokine secretion, and cytolytic function. Although a [...] Read more.
Programmed cell death-1 (PD-1) is a cell surface receptor that dampens adaptive immune responses. PD-1 is activated by the engagement of its ligands PDL-1 or PDL-2. This results in the inhibition of T cell proliferation, differentiation, cytokine secretion, and cytolytic function. Although a great deal is known about PD-1 mediated regulation of CD4+ and CD8+ T cells, its expression and function in innate lymphoid cells (ILCs) are yet to be fully deciphered. This review summarizes the role of PD-1 in (1) modulating ILC development, (2) ILC function, and (3) PD-1 signaling in ILC. Finally, we explore how PD-1 based immunotherapies may be beneficial in boosting ILC responses in cancer, infections, and other immune-related disorders. Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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Open AccessReview
Hyperprogression under Immunotherapy
Int. J. Mol. Sci. 2019, 20(11), 2674; https://doi.org/10.3390/ijms20112674 - 30 May 2019
Cited by 18
Abstract
Immunotherapy is now widely prescribed in oncology, leading to the observation of new types of responses, including rapid disease progression sometimes reported as hyperprogression. However, only a few studies have assessed the question of hyperprogression and there is no consensual definition of this [...] Read more.
Immunotherapy is now widely prescribed in oncology, leading to the observation of new types of responses, including rapid disease progression sometimes reported as hyperprogression. However, only a few studies have assessed the question of hyperprogression and there is no consensual definition of this phenomenon. We reviewed existing data on hyperprogression in published studies, focusing on reported definitions, predictive factors, and potential biological mechanisms. Seven studies retrospectively assessed hyperprogression incidence, using various definitions, some based on the tumoral burden variation across time with repeated computed-tomography (CT) scan, others based on an association of radiological and clinical criteria. Reported hyperprogression incidence varied between 4% and 29% of all responses, mostly in multi-tumor cohorts and with patients receiving immune checkpoint inhibitors. Hyperprogression correlated with worse chances of survival than standard progression in two studies. However, no strong predictive factors of hyperprogression were identified, and none were consistent across studies. In total, hyperprogression is a frequent pattern of response under immunotherapy, with a strong impact on patient outcome. There is a need for a consensual definition of hyperprogression. Immunotherapy should be stopped early in cases where there is suspicion of hyperprogression. Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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Open AccessReview
Programmed Cell Death 1 (PD-1) Inhibitors in Renal Transplant Patients with Advanced Cancer: A Double-Edged Sword?
Int. J. Mol. Sci. 2019, 20(9), 2194; https://doi.org/10.3390/ijms20092194 - 03 May 2019
Cited by 7
Abstract
Given advancements in cancer immunity, cancer treatment has gained breakthrough developments. Immune checkpoint inhibitors, such as programmed cell death 1 (PD-1) inhibitors, are the most promising drugs in the field and have been approved to treat various types of cancer, such as metastatic [...] Read more.
Given advancements in cancer immunity, cancer treatment has gained breakthrough developments. Immune checkpoint inhibitors, such as programmed cell death 1 (PD-1) inhibitors, are the most promising drugs in the field and have been approved to treat various types of cancer, such as metastatic melanoma, head and neck squamous cell carcinoma, and urothelial carcinoma. However, whether PD-1 inhibitors should be administered to renal transplant patients with advanced cancer remains unclear because the T-cells produced after administration of these inhibitors act against not only tumor antigens but also donor alloantigens. Thus, the use of PD-1 inhibitors in kidney-transplanted patients with advanced cancer is limited on account of the high risk of graft failure due to acute rejection. Hence, finding optimal treatment regimens to enhance the tumor-specific T-cell response and decrease T-cell-mediated alloreactivity after administration of a PD-1 inhibitor is necessary. Thus far, no recommendations for the use of PD-1 inhibitors to treat cancer in renal transplant patients are yet available, and very few cases reporting kidney-transplanted patients treated with PD-1 inhibitors are available in the literature. Therefore, in this work, we review the published cases and suggest feasible approaches for renal transplant patients with advanced malignancy treated by a PD-1 inhibitor. Of the 22 cases we obtained, four patients maintained intact grafts without tumor progression after treatment with a PD-1 inhibitor. Among these patients, one maintained steroid dose before initiation of anti-PD1, two received immunosuppressive regimens with low-dose steroid and calcineurin inhibitor (CNI)-elimination with sirolimus before initiation of anti-PD-1 therapy, and one received combined anti-PD-1, anti-vascular endothelial growth factor (VEGF), and chemotherapy with unchanged immunosuppressive regimens. mammalian target of rapamycin (mTOR) inhibitors and anti-VEGF may act as regulators of tumor-specific and allogenic T-cells. However, more studies are necessary to explore the optimal therapy and ensure the safety and efficacy of PD-1 inhibitors in kidney-transplanted patients. Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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Open AccessReview
Beyond PD-L1 Markers for Lung Cancer Immunotherapy
Int. J. Mol. Sci. 2019, 20(8), 1915; https://doi.org/10.3390/ijms20081915 - 18 Apr 2019
Cited by 18
Abstract
Immunotherapy using immune checkpoints inhibitors has become the standard treatment for first and second line therapy in patients with non-small cell lung cancer (NSCLC). However, proper predictive factors allowing precise qualification of NSCLC patients for immunotherapy have not been developed so far. Expression [...] Read more.
Immunotherapy using immune checkpoints inhibitors has become the standard treatment for first and second line therapy in patients with non-small cell lung cancer (NSCLC). However, proper predictive factors allowing precise qualification of NSCLC patients for immunotherapy have not been developed so far. Expression of PD-L1 on tumor cells and tumor mutation burden are used in qualification of patients to first line therapy with pembrolizumab and atezolizumab in combination with ipilimumab in prospective clinical trials. Nevertheless, not all patients with these predictive factors benefit from immunotherapy. Major methodological difficulties in testing of these factors and in the interpretation of test results still exist. Therefore, other predictive factors are sought. Intensive research on the recognition of tumor immunophenotype and gut microbiome in NSCLC patients are underway. The first correlations between the effectiveness of immunotherapy and the intensity of inflammatory response in the tumor, microbiome diversity, and the occurrence of certain bacterial species in gut have been described. The purpose of our manuscript is to draw attention to factors affecting the efficacy of immunotherapy with anti-PD-L1 antibodies in NSCLC patients. Additional markers, for example TMB (tumor mutations burden) or microbiome profile, are needed to more accurately determine which patients will benefit from immunotherapy treatment. Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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Open AccessReview
Targeting the PD-1/PD-L1 Pathway in Renal Cell Carcinoma
Int. J. Mol. Sci. 2019, 20(7), 1692; https://doi.org/10.3390/ijms20071692 - 04 Apr 2019
Cited by 17
Abstract
Renal cell carcinoma encompass distinct diseases with different pathologic features and distinct molecular pathways. Immune checkpoint inhibitors targeting the programmed death receptor ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) pathway alone or in combination have greatly changed clinical management of metastatic renal cell [...] Read more.
Renal cell carcinoma encompass distinct diseases with different pathologic features and distinct molecular pathways. Immune checkpoint inhibitors targeting the programmed death receptor ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) pathway alone or in combination have greatly changed clinical management of metastatic renal cell carcinoma, now competing with antiangiogenic drugs in monotherapy for first-line treatment. However, long-term response rates are low, and biomarkers are needed to predict treatment response. Quantification of PD-L1 expression by immunohistochemistry was developed as a promising biomarker in clinical trials, but with many limitations (different antibodies, tumour heterogeneity, specimens, and different thresholds of positivity). Other biomarkers, including tumour mutational burden and molecular signatures, are also developed and discussed in this review. Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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Open AccessReview
Glial Cell Expression of PD-L1
Int. J. Mol. Sci. 2019, 20(7), 1677; https://doi.org/10.3390/ijms20071677 - 04 Apr 2019
Cited by 2
Abstract
The programmed death (PD)-1/PD-L1 pathway is a well-recognized negative immune checkpoint that results in functional inhibition of T-cells. Microglia, the brain-resident immune cells are vital for pathogen detection and initiation of neuroimmune responses. Moreover, microglial cells and astrocytes govern the activity of brain-infiltrating [...] Read more.
The programmed death (PD)-1/PD-L1 pathway is a well-recognized negative immune checkpoint that results in functional inhibition of T-cells. Microglia, the brain-resident immune cells are vital for pathogen detection and initiation of neuroimmune responses. Moreover, microglial cells and astrocytes govern the activity of brain-infiltrating antiviral T-cells through upregulation of PD-L1 expression. While T-cell suppressive responses within brain are undoubtedly beneficial to the host, preventing cytotoxic damage to this vital organ, establishment of a prolonged anti-inflammatory milieu may simultaneously lead to deficiencies in viral clearance. An immune checkpoint blockade targeting the PD-1: PD-L1 (B7-H1; CD274) axis has revolutionized contemporary treatment for a variety of cancers. However, the therapeutic potential of PD1: PD-L1 blockade therapies targeting viral brain reservoirs remains to be determined. For these reasons, it is key to understand both the detrimental and protective functions of this signaling pathway within the brain. This review highlights how glial cells use PD-L1 expression to modulate T-cell effector function and limit detrimental bystander damage, while still retaining an effective defense of the brain. Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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Open AccessReview
PD-1 Ligand Expression in Epithelial Thyroid Cancers: Potential Clinical Implications
Int. J. Mol. Sci. 2019, 20(6), 1405; https://doi.org/10.3390/ijms20061405 - 20 Mar 2019
Cited by 14
Abstract
The new immunotherapy targeting the programmed cell death 1 (PD-1) receptor and its cognate ligand PD-L1 has renewed hopes of eradicating the most difficult human cancers to treat. Among these, there are the poorly differentiated and anaplastic thyroid cancers, unresponsive to all the [...] Read more.
The new immunotherapy targeting the programmed cell death 1 (PD-1) receptor and its cognate ligand PD-L1 has renewed hopes of eradicating the most difficult human cancers to treat. Among these, there are the poorly differentiated and anaplastic thyroid cancers, unresponsive to all the therapies currently in use. In the present review we will summarize information regarding the expression of PD-L1 in the different thyroid cancer histotypes, its correlation with clinicopathological features, and its potential prognostic value. Then, we will evaluate the available data indicating the PD-1/PD-L1 axis as a promising target for thyroid cancer therapy. Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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Other

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Open AccessCase Report
Remarkable Alteration of PD-L1 Expression after Immune Checkpoint Therapy in Patients with Non-Small-Cell Lung Cancer: Two Autopsy Case Reports
Int. J. Mol. Sci. 2019, 20(10), 2578; https://doi.org/10.3390/ijms20102578 - 26 May 2019
Cited by 5
Abstract
Pembrolizumab is an immune checkpoint inhibitor (ICI), currently recommended as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) showing ≥50% expression of programmed death-ligand 1 (PD-L1). Previously it was reported that platinum-based chemotherapy may change PD-L1 expression in solid cancers. [...] Read more.
Pembrolizumab is an immune checkpoint inhibitor (ICI), currently recommended as the first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) showing ≥50% expression of programmed death-ligand 1 (PD-L1). Previously it was reported that platinum-based chemotherapy may change PD-L1 expression in solid cancers. However, no reports addressing alteration of PD-L1 expression after ICI therapy in NSCLC are available so far. The patients were Japanese males 83 and 87 years old, who were diagnosed with NSCLC based on the transbronchial lung biopsies showing sarcomatoid feature with high PD-L1 expression. They received Pembrolizumab, however, passed away with disease progression on day 27 and day 9, respectively. PD-L1, PD1, and CD8 antibodies were applied to pretreatment tumor biopsies and autopsy specimens. Immunoexpression of all the markers was evaluated using Aperio ImageScope. We found that PD-L1 expression decreased significantly from 75.6% to 13.2% and from 100% to 58.8%, in patients 1 and 2, respectively. This alteration was less prominent in the perinecrotic tumor area. A considerable decrease of PD-L1 score was linked with a little effect of Pembrolizumab in our patients. This association might be one of the contributing mechanisms of resistance to ICI and needs further investigation in large-scale studies. Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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