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PD-L1, a Master Regulator of Immunity 2.0
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PD-L1, a Master Regulator of Immunity 2.0

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 (30 April 2022) | Viewed by 50811

Special Issue Editor

Dr. Grazyna Kochan

E-Mail Website
Guest Editor
Oncoimmunology Group, Biomedical Research Center of Navarre‐Navarrabiomed, Fundación Miguel Servet, IdISNA, Pamplona, Spain
Interests: PD-L1; biomarker; lung cancer; immunotherapy; immune checkpoint blockade
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Programmed cell death ligand (PD-L1) is a co-inhibitory molecule that is expressed on immune cells and cancer cells. Through binding with its receptor, programmed death 1 (PD-1) on the T cell surface, regulates their activity. In that way, adaptive immune responses mediated by T cells against invading pathogens are strictly regulated, thereby avoiding collateral damage to the host. However, this regulatory circuit is dysregulated in several diseases as chronic infection, transplantation immunity, autoimmunity, and cancer to dampen immune responses prematurely. Blocking the PD-1:PD-L1 immune checkpoint axis has, therefore, garnered substantial interest especially in oncology. In cancer, PD-1:PD-L1 blockade has resulted in unprecedented successes in individual patients across a variety of cancer types. However, a large number of patients fail to respond to PD-1:PD-L1 blockade. Insights into different mechanisms underlying this therapy failure are gradually being gained. These insights highlight the complexity of the immune system regulatory interaction with cancer cells. Numerous studies have begun to shed light on how combination with other therapies could enhance the response rates to PD-1:PD-L1 blockade.

Dr. Grazyna Kochan
Guest Editor

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Keywords

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

Published Papers (15 papers)

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Research

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18 pages, 2841 KiB  
Article
Differential Expression of PD-L1 during Cell Cycle Progression of Head and Neck Squamous Cell Carcinoma
by Daniela Schulz, Martin Wetzel, Jonas Eichberger, Gerhard Piendl, Gero Brockhoff, Anja K. Wege, Torsten E. Reichert, Tobias Ettl and Richard J. Bauer
Int. J. Mol. Sci. 2021, 22(23), 13087; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313087 - 03 Dec 2021
Cited by 7 | Viewed by 2121
Abstract
The expression of PD-L1 by tumor cells is mainly associated with its immunosuppressive effect. In fact, PD-1/PD-L1 immune checkpoint inhibitors demonstrated remarkable effects in advanced cancer patients including HNSCC. In this context, irradiation is currently being investigated as a synergistic treatment modality to [...] Read more.
The expression of PD-L1 by tumor cells is mainly associated with its immunosuppressive effect. In fact, PD-1/PD-L1 immune checkpoint inhibitors demonstrated remarkable effects in advanced cancer patients including HNSCC. In this context, irradiation is currently being investigated as a synergistic treatment modality to immunotherapy. However, the majority of HNSCC patients still show little improvement or even hyperprogression. Interestingly, there is increasing evidence for additional cell-intrinsic functions of PD-L1 in tumor cells. In previous studies, we showed that PD-L1 has a strong influence on proliferation, migration, invasion, and survival after irradiation. We demonstrated that cellular expression and localization of PD-L1 differed depending on sensitivity to irradiation. Here, we show that PD-L1 is also differentially expressed during cell cycle progression of HNSCC. Furthermore, cellular localization of PD-L1 also changes depending on a particular cell cycle phase. Moreover, distinct observations occurred depending on the general differentiation status. Overall, the function of PD-L1 cannot be generalized. Rather, it depends on the differentiation status and microenvironment. PD-L1 expression and localization are variable, depending on different factors. These findings may provide insight into why differential response to PD-1/PD-L1 antibody therapy can occur. Detailed understanding of cell-intrinsic PD-L1 functions will further allow antibody-based immunotherapy to be optimized. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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15 pages, 2488 KiB  
Article
Tumor-Derived Small Extracellular Vesicles Induce Pro-Inflammatory Cytokine Expression and PD-L1 Regulation in M0 Macrophages via IL-6/STAT3 and TLR4 Signaling Pathways
by Marzia Pucci, Stefania Raimondo, Ornella Urzì, Marta Moschetti, Maria Antonietta Di Bella, Alice Conigliaro, Nadia Caccamo, Marco Pio La Manna, Simona Fontana and Riccardo Alessandro
Int. J. Mol. Sci. 2021, 22(22), 12118; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212118 - 09 Nov 2021
Cited by 24 | Viewed by 3061
Abstract
Tumor-associated macrophages play a key role in promoting tumor progression by exerting an immunosuppressive phenotype associated with the expression of programmed cell death ligand 1 (PD-L1). It is well known that tumor-derived small extracellular vesicles (SEVs) affect the tumor microenvironment, influencing TAM behavior. [...] Read more.
Tumor-associated macrophages play a key role in promoting tumor progression by exerting an immunosuppressive phenotype associated with the expression of programmed cell death ligand 1 (PD-L1). It is well known that tumor-derived small extracellular vesicles (SEVs) affect the tumor microenvironment, influencing TAM behavior. The present study aimed to examine the effect of SEVs derived from colon cancer and multiple myeloma cells on macrophage functions. Non-polarized macrophages (M0) differentiated from THP-1 cells were co-cultured with SEVs derived from a colorectal cancer (CRC) cell line, SW480, and a multiple myeloma (MM) cell line, MM1.S. The expression of PD-L1, interleukin-6 (IL-6), and other inflammatory cytokines as well as of the underlying molecular mechanisms were evaluated. Our results indicate that SEVs can significantly upregulate the expressions of PD-L1 and IL-6 at both the mRNA and protein levels and can activate the STAT3 signaling pathway. Furthermore, we identified the TLR4/NF-kB pathway as a convergent mechanism for SEV-mediated PD-L1 expression. Overall, these preliminary data suggest that SEVs contribute to the formation of an immunosuppressive microenvironment. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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24 pages, 3910 KiB  
Article
Clinical and Prognostic Value of Antigen-Presenting Cells with PD-L1/PD-L2 Expression in Ovarian Cancer Patients
by Anna Pawłowska, Agnieszka Kwiatkowska, Dorota Suszczyk, Agata Chudzik, Rafał Tarkowski, Bartłomiej Barczyński, Jan Kotarski and Iwona Wertel
Int. J. Mol. Sci. 2021, 22(21), 11563; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111563 - 26 Oct 2021
Cited by 17 | Viewed by 2555
Abstract
The latest literature demonstrates the predominant role of the programmed cell death axis (PD-1/PD-L1/PD-L2) in ovarian cancer (OC) pathogenesis. However, data concerning this issue is ambiguous. Our research aimed to evaluate the clinical importance of PD-L1/PD-L2 expression in OC environments. We evaluated the [...] Read more.
The latest literature demonstrates the predominant role of the programmed cell death axis (PD-1/PD-L1/PD-L2) in ovarian cancer (OC) pathogenesis. However, data concerning this issue is ambiguous. Our research aimed to evaluate the clinical importance of PD-L1/PD-L2 expression in OC environments. We evaluated the role of PD-L1/PD-L2 in OC patients (n = 53). The analysis was performed via flow cytometry on myeloid (mDCs) and plasmacytoid dendritic cells (pDCs) and monocytes/macrophages (MO/MA) in peripheral blood, peritoneal fluid (PF), and tumor tissue (TT). The data were correlated with clinicopathological characteristics and prognosis of OC patients. The concentration of soluble PD-L1 (sPD-L1) and PD-1 in the plasma and PF were determined by ELISA. We established an accumulation of PD-L1+/PD-L2+ mDCs, pDCs, and MA in the tumor microenvironment. We showed an elevated level of sPD-L1 in the PF of OC patients in comparison to plasma and healthy subjects. sPD-L1 levels in PF showed a positive relationship with Ca125 concentration. Moreover, we established an association between higher sPD-L1 levels in PF and shorter survival of OC patients. An accumulation of PD-L1+/PD-L2+ mDCs, pDCs, and MA in the TT and high sPD-L1 levels in PF could represent the hallmark of immune regulation in OC patients. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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11 pages, 4812 KiB  
Article
Reconstitution of Monocyte Subsets and PD-L1 Expression but Not T Cell PD-1 Expression in Obstructive Sleep Apnea Patients upon PAP Therapy
by Christina Polasky, Armin Steffen, Kristin Loyal, Christian Lange, Karl-Ludwig Bruchhage and Ralph Pries
Int. J. Mol. Sci. 2021, 22(21), 11375; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111375 - 21 Oct 2021
Cited by 6 | Viewed by 1689
Abstract
Obstructive sleep apnea (OSA) is characterized by nocturnal breathing intermissions resulting in oxidative stress and eventually, a low-grade systemic inflammation. The study aimed to investigate the impact of positive airway pressure (PAP) therapy on the inflammatory milieu as measured by monocyte and T [...] Read more.
Obstructive sleep apnea (OSA) is characterized by nocturnal breathing intermissions resulting in oxidative stress and eventually, a low-grade systemic inflammation. The study aimed to investigate the impact of positive airway pressure (PAP) therapy on the inflammatory milieu as measured by monocyte and T cell phenotypic alterations. Participants were assessed for their OSA severity before PAP therapy and about six months later, including patient-reported outcome and therapy usage by telemetry readout. The distributions of the CD14/CD16-characterized monocyte subsets as well as the CD4/CD8-characterized effector T cell subsets with regard to their PD-1 and PD-L1 expression were analyzed by flow cytometry from blood samples. Data of 25 patients revealed a significant reconstitution of the monocyte subset distribution and a decrease in PD-L1 expression on pan-monocytes and CD8+ T cells without an association to initial AHI and overweight. The PD-1 expression was still increased on T cell subsets, especially on CD4+ TH17/22 cells. We conclude that PAP therapy might have a rapid effect on the monocyte phenotype and overall PD-L1 expression levels. However, T cell immune alterations especially on TH17/22 cells persist longer, indicating an ongoing disturbance of the adaptive immune system. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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10 pages, 539 KiB  
Article
PD-L1 Status in Gastric Cancers, Association with the Transcriptional, Growth Factors, AKT/mTOR Components Change, and Autophagy Initiation
by Liudmila Spirina, Alexandra Avgustinovich, Sergei Afanas’ev, Maxim Volkov, Alexey Dobrodeev, Olga Cheremisina and Dmitry Kostromitsky
Int. J. Mol. Sci. 2021, 22(20), 11176; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011176 - 16 Oct 2021
Cited by 6 | Viewed by 2274
Abstract
Introduction: The programmed death receptor ligand 1 (PD-L1) immunohistochemistry (IHC) assay is a widely used selection method for pembrolizumab treatment in gastric cancer (GC) patients. PD-L1 is the main regulator of immunity in oncogenesis. Material and methods: The study included 38 patients with [...] Read more.
Introduction: The programmed death receptor ligand 1 (PD-L1) immunohistochemistry (IHC) assay is a widely used selection method for pembrolizumab treatment in gastric cancer (GC) patients. PD-L1 is the main regulator of immunity in oncogenesis. Material and methods: The study included 38 patients with GC. The combined treatment consisted of neoadjuvant FOLFOX6, or FLOT, chemotherapy and surgery. PD-L1 + tumor status was recorded in 12 patients (CPS > 5), with a negative status recorded in 26 patients. RT-PCR determined the expression of molecular markers. The level of LC3B protein was detected by Western Blotting analysis. Results: An overexpression of PD-1, PD-L2 in the tumor is associated with AKT/mTOR mRNA profile change and autophagy initiation in IHC PD-L1 positive GCs. NACT influences these biological features, modifying the expression of AKT/mTOR components and autophagic flux. In PD-L1 positive cancers, the effect of NACT and molecular markers rearrangements are essential compared to the PD-L1 negative cancers. Conclusion: The IHC PD-L1 status in gastric cancers is the significant marker of cancer progression, recovering the multiple inner mechanisms of cancer spreading and leading to ineffective therapy. Autophagy induction and angiogenesis are found in PD-L1 positive gastric cancers. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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11 pages, 6509 KiB  
Article
Levels of Circulating PD-L1 Are Decreased in Patients with Resectable Cholangiocarcinoma
by Christoph Roderburg, Sven H. Loosen, Jan Bednarsch, Patrick H. Alizai, Anjali A. Roeth, Sophia M. Schmitz, Mihael Vucur, Mark Luedde, Pia Paffenholz, Frank Tacke, Christian Trautwein, Tom F. Ulmer, Ulf Peter Neumann and Tom Luedde
Int. J. Mol. Sci. 2021, 22(12), 6569; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126569 - 18 Jun 2021
Cited by 4 | Viewed by 2295
Abstract
Tumor resection represents the only curative treatment option for patients with biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (CCA), perihilar and extrahepatic CCA and gallbladder cancer. However, many patients develop early tumor recurrence and are unlikely to benefit from surgery. Therefore, markers to [...] Read more.
Tumor resection represents the only curative treatment option for patients with biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (CCA), perihilar and extrahepatic CCA and gallbladder cancer. However, many patients develop early tumor recurrence and are unlikely to benefit from surgery. Therefore, markers to identify ideal surgical candidates are urgently needed. Circulating programmed cell death 1 ligand 1 (PD-L1) has recently been associated with different malignancies, including pancreatic cancer which closely resembles BTC in terms of patients’ prognosis and tumor biology. Here, we aim at evaluating a potential role of circulating PD-L1 as a novel biomarker for resectable BTC. Methods: Serum levels of PD-L1 were analyzed by ELISA in 73 BTC patients and 42 healthy controls. Results: Circulating levels of preoperative PD-L1 were significantly lower in patients with BTC compared to controls. Patients with low PD-L1 levels displayed a strong trend towards an impaired prognosis, and circulating PD-L1 was negatively correlated with experimental markers of promalignant tumor characteristics such as CCL1, CCL21, CCL25 and CCL26. For 37 out of 73 patients, postoperative PD-L1 levels were available. Interestingly, after tumor resection, circulating PD-L1 raised to almost normal levels. Notably, patients with further decreasing PD-L1 concentrations after surgery showed a trend towards an impaired postoperative outcome. Conclusion: Circulating PD-L1 levels were decreased in patients with resectable BTC. Lack of normalization of PD-L1 levels after surgery might identify patients at high risk for tumor recurrence or adverse outcome. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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14 pages, 674 KiB  
Article
PD-1 and PD-L1 Expression on Circulating Lymphocytes as a Marker of Epstein-Barr Virus Reactivation-Associated Proliferative Glomerulonephritis
by Ewelina Grywalska, Iwona Smarz-Widelska, Izabela Korona-Głowniak, Sebastian Mertowski, Krzysztof Gosik, Anna Hymos, Jarosław Ludian, Paulina Niedźwiedzka-Rystwej, Jacek Roliński and Wojciech Załuska
Int. J. Mol. Sci. 2020, 21(21), 8001; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218001 - 27 Oct 2020
Cited by 8 | Viewed by 2514
Abstract
Alterations to the programmed cell death protein-1 (PD-1) pathway were previously shown to be involved in a poorer prognosis for patients with proliferative glomerulonephritis (PGN). Here, we investigated the association between several infectious agents and the expression of PD-1 and its ligand (PD-L1) [...] Read more.
Alterations to the programmed cell death protein-1 (PD-1) pathway were previously shown to be involved in a poorer prognosis for patients with proliferative glomerulonephritis (PGN). Here, we investigated the association between several infectious agents and the expression of PD-1 and its ligand (PD-L1) on T and B lymphocytes in patients with PGN and nonproliferative glomerulonephritis (NPGN). A cohort of 45 newly-diagnosed patients (23 with PGN and 22 with NPGN) and 20 healthy volunteers was enrolled. The percentage of peripheral blood mononuclear cells expressing PD-1 and PD-L1 antigens was determined by flow cytometry. We found PD-1 and PD-L1 expression on T and B lymphocytes was higher in PGN patients than in NPGN patients and controls. We also found that reactivation of the Epstein-Barr virus (EBV) correlated with the expression of PD-1/PD-L1 antigens in patients with PGN. Further receiver operating characteristic analysis indicated that PD-1 expression could distinguish EBV-positive PGN patients from those with NPGN or healthy controls. The use of PD-1 expression as a non-invasive marker of PGN should be further investigated. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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Review

Jump to: Research

25 pages, 1573 KiB  
Review
Beyond Cancer: Regulation and Function of PD-L1 in Health and Immune-Related Diseases
by Amke C. Beenen, Tatjana Sauerer, Niels Schaft and Jan Dörrie
Int. J. Mol. Sci. 2022, 23(15), 8599; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158599 - 02 Aug 2022
Cited by 11 | Viewed by 2917
Abstract
Programmed Cell Death 1 Ligand 1 (PD-L1, CD274, B7-H1) is a transmembrane protein which is strongly involved in immune modulation, serving as checkpoint regulator. Interaction with its receptor, Programmed Cell Death Protein 1 (PD-1), induces an immune-suppressive signal, which modulates the activity of [...] Read more.
Programmed Cell Death 1 Ligand 1 (PD-L1, CD274, B7-H1) is a transmembrane protein which is strongly involved in immune modulation, serving as checkpoint regulator. Interaction with its receptor, Programmed Cell Death Protein 1 (PD-1), induces an immune-suppressive signal, which modulates the activity of T cells and other effector cells. This mediates peripheral tolerance and contributes to tumor immune escape. PD-L1 became famous due to its deployment in cancer therapy, where blockage of PD-L1 with the help of therapeutic antagonistic antibodies achieved impressive clinical responses by reactivating effector cell functions against tumor cells. Therefore, in the past, the focus has been placed on PD-L1 expression and its function in various malignant cells, whereas its role in healthy tissue and diseases apart from cancer remained largely neglected. In this review, we summarize the function of PD-L1 in non-cancerous cells, outlining its discovery and origin, as well as its involvement in different cellular and immune-related processes. We provide an overview of transcriptional and translational regulation, and expression patterns of PD-L1 in different cells and organs, and illuminate the involvement of PD-L1 in different autoimmune diseases as well as in the context of transplantation and pregnancy. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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18 pages, 753 KiB  
Review
PD-1/PD-L1, MDSC Pathways, and Checkpoint Inhibitor Therapy in Ph(-) Myeloproliferative Neoplasm: A Review
by Jen-Chin Wang and Lishi Sun
Int. J. Mol. Sci. 2022, 23(10), 5837; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105837 - 23 May 2022
Cited by 8 | Viewed by 3265
Abstract
There has been significant progress in immune checkpoint inhibitor (CPI) therapy in many solid tumor types. However, only a single failed study has been published in treating Ph(-) myeloproliferative neoplasm (MPN). To make progress in CPI studies on this disease, herein, we [...] Read more.
There has been significant progress in immune checkpoint inhibitor (CPI) therapy in many solid tumor types. However, only a single failed study has been published in treating Ph(-) myeloproliferative neoplasm (MPN). To make progress in CPI studies on this disease, herein, we review and summarize the mechanisms of activation of the PD-L1 promoter, which are as follows: (a) the extrinsic mechanism, which is activated by interferon gamma (IFN γ) by tumor infiltration lymphocytes (TIL) and NK cells; (b) the intrinsic mechanism of EGFR or PTEN loss resulting in the activation of the MAPK and AKT pathways and then stat 1 and 3 activation; and (c) 9p24 amplicon amplification, resulting in PD-L1 and Jak2 activation. We also review the literature and postulate that many of the failures of CPI therapy in MPN are likely due to excessive MDSC activities. We list all of the anti-MDSC agents, especially those with ruxolitinib, IMID compounds, and BTK inhibitors, which may be combined with CPI therapy in the future as part of clinical trials applying CPI therapy to Ph(-) MPN. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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15 pages, 808 KiB  
Review
Current Immunotherapeutic Strategies Targeting the PD-1/PD-L1 Axis in Non-Small Cell Lung Cancer with Oncogenic Driver Mutations
by Ichidai Tanaka and Masahiro Morise
Int. J. Mol. Sci. 2022, 23(1), 245; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010245 - 27 Dec 2021
Cited by 7 | Viewed by 3409
Abstract
Treatment strategies targeting programed cell death 1 (PD-1) or its ligand, PD-L1, have been developed as immunotherapy against tumor progression for various cancer types including non-small cell lung cancer (NSCLC). The recent pivotal clinical trials of immune-checkpoint inhibiters (ICIs) combined with cytotoxic chemotherapy [...] Read more.
Treatment strategies targeting programed cell death 1 (PD-1) or its ligand, PD-L1, have been developed as immunotherapy against tumor progression for various cancer types including non-small cell lung cancer (NSCLC). The recent pivotal clinical trials of immune-checkpoint inhibiters (ICIs) combined with cytotoxic chemotherapy have reshaped therapeutic strategies and established various first-line standard treatments. The therapeutic effects of ICIs in these clinical trials were analyzed according to PD-L1 tumor proportion scores or tumor mutational burden; however, these indicators are insufficient to predict the clinical outcome. Consequently, molecular biological approaches, including multi-omics analyses, have addressed other mechanisms of cancer immune escape and have revealed an association of NSCLC containing specific driver mutations with distinct immune phenotypes. NSCLC has been characterized by driver mutation-defined molecular subsets and the effect of driver mutations on the regulatory mechanism of PD-L1 expression on the tumor itself. In this review, we summarize the results of recent clinical trials of ICIs in advanced NSCLC and the association between driver alterations and distinct immune phenotypes. We further discuss the current clinical issues with a future perspective for the role of precision medicine in NSCLC. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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19 pages, 1524 KiB  
Review
New Insights into the Role of PD-1 and Its Ligands in Allergic Disease
by Miguel Angel Galván Morales, Josaphat Miguel Montero-Vargas, Juan Carlos Vizuet-de-Rueda and Luis M Teran
Int. J. Mol. Sci. 2021, 22(21), 11898; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111898 - 02 Nov 2021
Cited by 12 | Viewed by 3366
Abstract
Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2 are receptors that act in co-stimulatory and coinhibitory immune responses. Signaling the PD-1/PD-L1 or PD-L2 pathway is essential to regulate the inflammatory responses to infections, autoimmunity, and allergies, and it has been [...] Read more.
Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2 are receptors that act in co-stimulatory and coinhibitory immune responses. Signaling the PD-1/PD-L1 or PD-L2 pathway is essential to regulate the inflammatory responses to infections, autoimmunity, and allergies, and it has been extensively studied in cancer. Allergic diseases include asthma, rhinoconjunctivitis, atopic dermatitis, drug allergy, and anaphylaxis. These overactive immune responses involve IgE-dependent activation and increased CD4+ T helper type 2 (Th2) lymphocytes. Recent studies have shown that PD-L1 and PD-L2 act to regulate T-cell activation and function. However, the main role of PD-1 and its ligands is to balance the immune response; however, the inflammatory process of allergic diseases is poorly understood. These immune checkpoint molecules can function as a brake or a kick-start to regulate the adaptive immune response. These findings suggest that PD-1 and its ligands may be a key factor in studying the exaggerated response in hypersensitivity reactions in allergies. This review summarizes the current understanding of the role of PD-1 and PD-L1 and PD-L2 pathway regulation in allergic diseases and how this immunomodulatory pathway is currently being targeted to develop novel therapeutic immunotherapy. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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16 pages, 730 KiB  
Review
Role of PD-L1 in Gut Mucosa Tolerance and Chronic Inflammation
by Marina Chulkina, Ellen J. Beswick and Irina V. Pinchuk
Int. J. Mol. Sci. 2020, 21(23), 9165; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239165 - 01 Dec 2020
Cited by 24 | Viewed by 3930
Abstract
The gastrointestinal (GI) mucosa is among the most complex systems in the body. It has a diverse commensal microbiome challenged continuously by food and microbial components while delivering essential nutrients and defending against pathogens. For these reasons, regulatory cells and receptors are likely [...] Read more.
The gastrointestinal (GI) mucosa is among the most complex systems in the body. It has a diverse commensal microbiome challenged continuously by food and microbial components while delivering essential nutrients and defending against pathogens. For these reasons, regulatory cells and receptors are likely to play a central role in maintaining the gut mucosal homeostasis. Recent lessons from cancer immunotherapy point out the critical role of the B7 negative co-stimulator PD-L1 in mucosal homeostasis. In this review, we summarize the current knowledge supporting the critical role of PD-L1 in gastrointestinal mucosal tolerance and how abnormalities in its expression and signaling contribute to gut inflammation and cancers. Abnormal expression of PD-L1 and/or the PD-1/PD-L1 signaling pathways have been observed in the pathology of the GI tract. We also discuss the current gap in our knowledge with regards to PD-L1 signaling in the GI tract under homeostasis and pathology. Finally, we summarize the current understanding of how this pathway is currently targeted to develop novel therapeutic approaches. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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30 pages, 1526 KiB  
Review
Delicate Role of PD-L1/PD-1 Axis in Blood Vessel Inflammatory Diseases: Current Insight and Future Significance
by Priya Veluswamy, Max Wacker, Maximilian Scherner and Jens Wippermann
Int. J. Mol. Sci. 2020, 21(21), 8159; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218159 - 31 Oct 2020
Cited by 22 | Viewed by 5332
Abstract
Immune checkpoint molecules are the antigen-independent generator of secondary signals that aid in maintaining the homeostasis of the immune system. The programmed death ligand-1 (PD-L1)/PD-1 axis is one among the most extensively studied immune-inhibitory checkpoint molecules, which delivers a negative signal for T [...] Read more.
Immune checkpoint molecules are the antigen-independent generator of secondary signals that aid in maintaining the homeostasis of the immune system. The programmed death ligand-1 (PD-L1)/PD-1 axis is one among the most extensively studied immune-inhibitory checkpoint molecules, which delivers a negative signal for T cell activation by binding to the PD-1 receptor. The general attributes of PD-L1’s immune-suppressive qualities and novel mechanisms on the barrier functions of vascular endothelium to regulate blood vessel-related inflammatory diseases are concisely reviewed. Though targeting the PD-1/PD-L1 axis has received immense recognition—the Nobel Prize in clinical oncology was awarded in the year 2018 for this discovery—the use of therapeutic modulating strategies for the PD-L1/PD-1 pathway in chronic inflammatory blood vessel diseases is still limited to experimental models. However, studies using clinical specimens that support the role of PD-1 and PD-L1 in patients with underlying atherosclerosis are also detailed. Of note, delicate balances in the expression levels of PD-L1 that are needed to preserve T cell immunity and to curtail acute as well as chronic infections in underlying blood vessel diseases are discussed. A significant link exists between altered lipid and glucose metabolism in different cells and the expression of PD-1/PD-L1 molecules, and its possible implications on vascular inflammation are justified. This review summarizes the most recent insights concerning the role of the PD-L1/PD-1 axis in vascular inflammation and, in addition, provides an overview exploring the novel therapeutic approaches and challenges of manipulating these immune checkpoint proteins, PD-1 and PD-L1, for suppressing blood vessel inflammation. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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23 pages, 1385 KiB  
Review
Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy
by Elena Shklovskaya and Helen Rizos
Int. J. Mol. Sci. 2020, 21(19), 7139; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197139 - 27 Sep 2020
Cited by 31 | Viewed by 5057
Abstract
Immunotherapies blocking immune inhibitory receptors programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) on T-cells have dramatically improved patient outcomes in a range of advanced cancers. However, the lack of response, and the development of resistance remain major obstacles to long-term improvements [...] Read more.
Immunotherapies blocking immune inhibitory receptors programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) on T-cells have dramatically improved patient outcomes in a range of advanced cancers. However, the lack of response, and the development of resistance remain major obstacles to long-term improvements in patient outcomes. There is significant interest in the clinical use of biomarkers to improve patient selection, and the expression of PD-1 ligand 1 (PD-L1) is often reported as a potential biomarker of response. However, accumulating evidence suggests that the predictive value of PD-L1 expression in tumor biopsies is relatively low due, in part, to its complex biology. In this review, we discuss the biological consequences of PD-L1 expression by various cell types within the tumor microenvironment, and the complex mechanisms that regulate PD-L1 expression at the genomic, transcriptomic and proteomic levels. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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17 pages, 499 KiB  
Review
PD-L1 in Systemic Immunity: Unraveling Its Contribution to PD-1/PD-L1 Blockade Immunotherapy
by Ana Bocanegra, Ester Blanco, Gonzalo Fernandez-Hinojal, Hugo Arasanz, Luisa Chocarro, Miren Zuazo, Pilar Morente, Ruth Vera, David Escors and Grazyna Kochan
Int. J. Mol. Sci. 2020, 21(16), 5918; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165918 - 18 Aug 2020
Cited by 14 | Viewed by 5392
Abstract
The use of monoclonal antibodies targeting PD-1/PD-L1 axis completely changed anticancer treatment strategies. However, despite the significant improvement in overall survival and progression-free survival of patients undergoing these immunotherapy treatments, the only clinically accepted biomarker with some prediction capabilities for the outcome of [...] Read more.
The use of monoclonal antibodies targeting PD-1/PD-L1 axis completely changed anticancer treatment strategies. However, despite the significant improvement in overall survival and progression-free survival of patients undergoing these immunotherapy treatments, the only clinically accepted biomarker with some prediction capabilities for the outcome of the treatment is PD-L1 expression in tumor biopsies. Nevertheless, even when having PD-L1-positive tumors, numerous patients do not respond to these treatments. Considering the high cost of these therapies and the risk of immune-related adverse events during therapy, it is necessary to identify additional biomarkers that would facilitate stratifying patients in potential responders and non-responders before the start of immunotherapies. Here, we review the utility of PD-L1 expression not only in tumor cells but in immune system cells and their influence on the antitumor activity of immune cell subsets. Full article
(This article belongs to the Special Issue PD-L1, a Master Regulator of Immunity 2.0)
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