Effects of Tumor-Derived Exosome Programmed Death Ligand 1 on Tumor Immunity and Clinical Applications

Programmed death ligand 1 (PD-L1) is a typical immune surface protein that binds to programmed cell death 1 (PD-1) on T cells through its extracellular domain. Subsequently, T cell activity is inhibited, and tumor immune tolerance is enhanced. Anti-PD-1/PD-L1 immune checkpoint therapy blocks the combination of PD-1/PD-L1 and rejuvenates depleted T cells, thereby inhibiting tumor growth. Exosomes are biologically active lipid bilayer nanovesicles secreted by various cell types, which mediate signal communication between cells. Studies have shown that PD-L1 can not only be expressed on the surface of tumor cells, immune cells, and other cells in the tumor microenvironment, but also be released from tumor cells and exist in an extracellular form. In particular, exosome PD-L1 plays an unfavorable role in tumor immunosuppression. The immunomodulatory effect of exosome PD-L1 and its potential in fluid diagnosis have attracted our attention. This review aims to summarize the available evidence regarding the biological characteristics of exosome PD-L1 in tumor immunity, with a particular focus on the mechanisms in different cancers and clinical prospects. In addition, we also summarized the current possible and effective detection methods for exosome PD-L1 and proposed that exosome PD-L1 has the potential to become a target for overcoming anti-PD-1/PD-L1 antibody treatment resistance.

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PD-L1 (Programmed Death Ligand 1) Regulates T-Cell Differentiation to Control Adaptive Venous Remodeling

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.316380 ◽

2021 ◽

Author(s):

Yutaka Matsubara ◽

Luis Gonzalez ◽

Gathe Kiwan ◽

Jia Liu ◽

John Langford ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nude Mice ◽

Cell Activity ◽

Vascular Wall ◽

Wall Thickening ◽

T Helper ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Helper Type

Objective: Patients with end-stage renal disease depend on hemodialysis for survival. Although arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis, the primary success rate of AVF is only 30% to 50% within 6 months, showing an urgent need for improvement. PD-L1 (programmed death ligand 1) is a ligand that regulates T-cell activity. Since T cells have an important role during AVF maturation, we hypothesized that PD-L1 regulates T cells to control venous remodeling that occurs during AVF maturation. Approach and results: In the mouse aortocaval fistula model, anti-PD-L1 antibody (200 mg, 3×/wk intraperitoneal) was given to inhibit PD-L1 activity during AVF maturation. Inhibition of PD-L1 increased T-helper type 1 cells and T-helper type 2 cells but reduced regulatory T cells to increase M1-type macrophages and reduce M2-type macrophages; these changes were associated with reduced vascular wall thickening and reduced AVF patency. Inhibition of PD-L1 also inhibited smooth muscle cell proliferation and increased endothelial dysfunction. The effects of anti-PD-L1 antibody on adaptive venous remodeling were diminished in nude mice; however, they were restored after T-cell transfer into nude mice, indicating the effects of anti-PD-L1 antibody on venous remodeling were dependent on T cells. Conclusions: Regulation of PD-L1 activity may be a potential therapeutic target for clinical translation to improve AVF maturation.

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Platelets up-Regulate Tumor Cell Programmed Death-Ligand 1 through Epidermal Growth Factor Receptor Signal Transduction

Blood ◽

10.1182/blood-2021-151339 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1006-1006

Author(s):

Qiuchen Guo ◽

Michael W Malloy ◽

Harvey G. Roweth ◽

Joseph E. Italiano ◽

Elisabeth Battinelli

Keyword(s):

Growth Factor ◽

Epidermal Growth Factor ◽

Tumor Cell ◽

Tumor Cells ◽

Tumor Immunity ◽

Cancer Cell Line ◽

Surface Expression ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Epidermal Growth

Abstract Introduction: Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are important immune checkpoint proteins in cancer immunotherapy and targeted therapies against PD-L1 have significantly prolonged many patients' lives. Recently, high baseline platelet to lymphocyte ratio was reported to be associated with decreased patient response rate to immune checkpoint inhibition (ICI) therapies, including anti-PD-L1 therapy, suggesting the potential role of platelets in tumor immunity. Platelets express PD-L1 on their surface, and platelets binding to PD-L1 negative tumor cells can "decorate" tumor cells with PD-L1 and protect against T cell-mediated cytotoxicity. However, whether platelet can affect PD-L1 expression on tumor cells is still unknown. Methods: In this study, we designed platelet-tumor cell co-culture systems to investigate whether direct or indirect exposure to platelets affects tumor cell PD-L1 surface expression. Considering platelets can be artificially activated by commonly used cell culture medium, the co-culture was performed in platelet resuspension buffer (HEPES, NaCl, KCl, MgCl2, NaHCO3, Glucose, pH7.4) supplied with fetal bovine serum and L-glutamine. After 24 hours of co-culture, platelets were washed out and fresh culturing medium was added to tumor cells and cultured for another 24 hours. At the end of the experiments, tumor cells were harvested and the PD-L1 expression analyzed by flow cytometry and RT-qPCR. Results and discussion: Here we report that direct co-culture of platelets with either breast cancer cell line MDA-MB-468 or lung cancer cell line A549 increased tumor cell PD-L1 surface expression by up-regulating PD-L1 transcription. This platelet-induced tumor cell PD-L1 up-regulation can be partly reduced by pre-treating platelets with antiplatelet agents such as aspirin and ticagrelor, suggesting platelet activation contributes to platelet induced tumor cell PD-L1 up-regulation. The up-regulation of tumor cell PD-L1 by platelets was not due to abundant platelet cytokines such as C-C Motif Chemokine Ligand 5 (CCL5) and C-X-C motif chemokine 5 (CXCL5). However, both an epidermal growth factor (EGF) neutralizing antibody and cetuximab (EGFR neutralizing monoclonal antibody) decreased the platelet-induced increase in tumor cell PD-L1, suggesting that platelets initiate tumor cell PD-L1 transcription through the EGF signaling pathway. Our data indicate a novel function of platelets in tumor immunity and warrant further investigation to determine if targeting platelets offers a novel adjuvant approach to improve ICI therapy. Disclosures Italiano: Sierra Oncology: Consultancy; PlateletBio: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Carrick Therapeutics: Consultancy.

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Optimal Evaluation of Programmed Death Ligand-1 on Tumor Cells Versus Immune Cells Requires Different Detection Methods

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2017-0159-oa ◽

2018 ◽

Vol 142 (8) ◽

pp. 982-991 ◽

Cited By ~ 16

Author(s):

Kelly A. Schats ◽

Emily A. Van Vré ◽

Carolien Boeckx ◽

Martine De Bie ◽

Dorien M. Schrijvers ◽

...

Keyword(s):

Tumor Cell ◽

Tumor Cells ◽

Immune Cells ◽

Immune Cell ◽

Detection Method ◽

Death Receptor ◽

Detection Methods ◽

Programmed Death Ligand 1 ◽

Cell Staining ◽

Programmed Death

Context.— The benefit of programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) as a method to select patients who may benefit from programmed death receptor-1 (PD-1)/PD-L1 immunotherapies remains uncertain in many tumor indications. Objectives.— To compare the commercially available, approved PD-L1 IHC assays (22C3, 28-8, SP142, SP263), specifically identifying the changes in staining output created by altering the detection method. Design.— This pilot study investigates the respective PD-L1 kit assay staining patterns and related scoring of tumor cells and immune cells on lung carcinoma and melanoma. Furthermore, the influence of the detection method (platform and related reagents) on PD-L1 antibody performance is studied. Results.— The SP142 kit reveals more immune cell staining but less tumor cell staining than the other PD-L1 kits. Alternatively, the 22C3 and 28-8 kits show good tumor cell sensitivity, but less pronounced immune cell staining, even in tonsil. Tumor cell staining by the SP263 kit is comparable to that of 22C3 and 28-8 kits, while immune cell staining is better. Strikingly, the selection of the detection method has a major impact on the sensitivity of the assay for PD-L1 detection per cell type. Switching the detection method of the kits could largely circumvent the observed staining differences. Conclusions.— The diverse sensitivities caused by the choice of the detection method should be taken into consideration when selecting PD-L1 kits or developing PD-L1 IHC laboratory-developed tests. When using alternative kits or laboratory-developed tests, it is strongly recommended to reestablish their clinical utility per therapeutic agent or compare them with the original kit.

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Programmed Death-Ligand 1 Protein and Colorectal Cancer Patient Survival Rates n Hasan Sadikin Hospital Bandung

BioScientia Medicina ◽

10.37275/bsm.v6i1.437 ◽

2021 ◽

Vol 6 (1) ◽

pp. 1300-1306

Author(s):

Vandra Bina Riyanda ◽

Reno Rudiman ◽

Nurhayat Usman

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

Cancer Patient ◽

Tumor Cells ◽

Patient Survival ◽

Survival Rates ◽

Men And Women ◽

Programmed Death Ligand 1 ◽

The Third ◽

Programmed Death

Background: According to the American Cancer Society, Colorectal Cancer (CRC) is the third leading cause of cancer death in men and women in the United States. In Indonesia, CRC ranks as the third most common malignancy in both men and women. Programmed death-ligand 1(PD-L1) is a trans-membrane receptor ligand and negative regulatory signal for T cells that is elevated in several tumors including CRC and binds to programmed death 1 (PD-1) on T cells, B cells, dendritic cells and natural killer T cells. PD-L1 expression was found in tumor cells and tumor cells that infiltrate immune cells in several malignancies, including CRC. Methods: This study is a comparative analytic cross sectional study with consecutive sampling method. This study was conducted at Hasan Sadikin Hospital, Bandung from September to October 2021. Further statistical analysis was done SPSS version 25.0 for Windows (SPSS Inc., Chicago, Ill., USA). Results: The total sample in this study was 50 subjects with colorectal cancer patients at RSHS. The number of CRC patients who expressed PD-L1 were 23 (46%) and 27 subjects (54%). The majority of cancer patient survival 2 Years was 38 subjects (76.0%) and survivors of more than 2 years was 12 subjects (24.0%). Conclusion: There is no significant relationship between PD-L1 and survival rates in CRC patients.

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A critical role for the programmed death ligand 1 in fetomaternal tolerance

Journal of Experimental Medicine ◽

10.1084/jem.20050019 ◽

2005 ◽

Vol 202 (2) ◽

pp. 231-237 ◽

Cited By ~ 263

Author(s):

Indira Guleria ◽

Arezou Khosroshahi ◽

Mohammed Javeed Ansari ◽

Antje Habicht ◽

Miyuki Azuma ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Critical Role ◽

Costimulatory Molecule ◽

Antibody Treatment ◽

Programmed Death Ligand 1 ◽

Fetal Survival ◽

Programmed Death ◽

Ifn Γ ◽

Rag 1

Fetal survival during gestation implies that tolerance mechanisms suppress the maternal immune response to paternally inherited alloantigens. Here we show that the inhibitory T cell costimulatory molecule, programmed death ligand 1 (PDL1), has an important role in conferring fetomaternal tolerance in an allogeneic pregnancy model. Blockade of PDL1 signaling during murine pregnancy resulted in increased rejection rates of allogeneic concepti but not syngeneic concepti. Fetal rejection was T cell– but not B cell–dependent because PDL1-specific antibody treatment caused fetal rejection in B cell–deficient but not in RAG-1–deficient females. Blockade of PDL1 also resulted in a significant increase in the frequency of IFN-γ–producing lymphocytes in response to alloantigen in an ELISPOT assay and higher IFN-γ levels in placental homogenates by ELISA. Finally, PDL1-deficient females exhibited decreased allogeneic fetal survival rates as compared with littermate and heterozygote controls and showed evidence of expansion of T helper type 1 immune responses in vivo. These results provide the first evidence that PDL1 is involved in fetomaternal tolerance.

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IMMU-06. COMBINATORIAL IMMUNE CHECKPOINT INHIBITORS FOR TARGETED INTRATUMORAL DELIVERY IN GBM

Neuro-Oncology ◽

10.1093/neuonc/noab196.366 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi93-vi93

Author(s):

Stephanie Sanders ◽

Denise Herpai ◽

Waldemar Debinski

Keyword(s):

T Cells ◽

Tumor Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cell Activity ◽

Live Cells ◽

Normal Brain ◽

Cytotoxic Therapies ◽

Checkpoint Receptors

Abstract Glioblastoma (GBM) is an immunologically cold tumor. Using single cell sequencing of CD45+ cells we confirmed that T cells are present within GBM samples. These T cells are positive for exhaustion markers such as LAG3 and TIGIT, as well as CTLA4 and PD1 checkpoint receptors. Modulating T cell activity through use of immune checkpoint inhibitors (ICIs) has shown efficacy in the treatment of a variety of solid tumors, and the combination of anti-CTLA4 and anti-PD1 ICIs has shown increased efficacy over use of a single therapeutic. Additionally, targeting ICIs to the tumor cells may increase efficacy of this treatment. We therefore constructed a combinatorial ICI redirected to GBM via interleukin 13 receptor alpha 2 (IL13RA2), a receptor over-expressed on the majority of GBM cells but not normal brain. The first component of the construct, labeled with a histidine tag, targets CTLA4 while the second component, tagged with a StrepII tag, targets PD1. The tags added to the constructs will allow for purification of a combinatorial heterodimer simultaneously targeting PD1, CTLA4 and IL13RA2. We purified individual components via fast protein liquid chromatography (FPLC) using a proteinG column followed by a HisTrap or StrepTrap column. We obtained a recombinant, targeted multivalent ICI at > 95% purity. We found that these constructs are able to bind their target receptors via ELISA in which the Kd values ranged from picomolar to low nanomolar range. Additionally, our constructs bind their target on live cells by flow cytometry. We next designed a heterodimeric construct which can combinatorially target CTLA4 and PD1 while also directing the ICI therapy to GBM. These constructs in conjunction with other immune stimulants like cytotoxic therapies are intended to facilitate the interaction between T cells and GBM tumor cells directly in a tumor microenvironment.

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Programmed Death Ligand-1 (PD-L1) Expression in Either Tumor Cells or Tumor-Infiltrating Immune Cells Correlates With Solid and High-Grade Lung Adenocarcinomas

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2017-0028-oa ◽

2017 ◽

Vol 141 (11) ◽

pp. 1529-1532 ◽

Cited By ~ 10

Author(s):

Brandon R. Driver ◽

Ross A. Miller ◽

Tara Miller ◽

Michael Deavers ◽

Blythe Gorman ◽

...

Keyword(s):

Tumor Cells ◽

Immune Cells ◽

Histologic Grade ◽

Fisher Exact Test ◽

Clinicopathologic Features ◽

Cell Lung Carcinoma ◽

Programmed Death Ligand 1 ◽

Exact Test ◽

Programmed Death ◽

High Histologic Grade

Context.— Programmed death ligand-1 (PD-L1) expression in non–small cell lung carcinoma (NSCLC) is heterogeneous and known to be underestimated on small biopsies. Correlation of PD-L1 expression with clinicopathologic features may provide additional useful information. To our knowledge, the clinicopathologic features of NSCLC have not been reported for subsets defined by PD-L1 expression in either tumor cells or tumor-infiltrating immune cells. Objective.— To investigate the clinicopathologic characteristics of NSCLC subsets defined by PD-L1 expression in either tumor cells or tumor-infiltrating immune cells. Design.— PD-L1 immunohistochemistry with the SP142 clone was performed on whole-tissue sections and given semiquantitative scores (0/1/2/3) according to percent of PD-L1+ tumor cells (TCs) and percent tumor area with PD-L1+ tumor-infiltrating immune cells (ICs). Results.— Adenocarcinoma cases that were scored either TC 1/2/3 or IC 1/2/3 included most (22 of 34; 65%) high–histologic grade cases and most (25 of 36; 69%) solid subtype cases. Compared with the adenocarcinoma TC 0 and IC 0 subset, the TC 1/2/3 or IC 1/2/3 subset correlated with higher histologic grade (P = .005, χ2 test for trend) and solid subtype (P < .001, Fisher exact test). Compared with the adenocarcinoma TC 0/1 or IC 0/1 subset, the TC 2/3 or IC 2/3 subset correlated with higher histologic grade (P = .002, χ2 test for trend), solid subtype (P < .001, Fisher exact test), and higher smoking pack-years (P = .01, Mann-Whitney test). Conclusions.— Lung adenocarcinoma subsets defined by PD-L1 expression in either tumor cells or tumor-infiltrating immune cells correlated with high histologic grade, solid subtype, and high smoking pack-years.

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