The immune checkpoint protein PD-L1 induces and maintains regulatory T cells in glioblastoma

DiDomenico, Joseph D.; Lamano, Jonathan B.; Oyon, Daniel E.; Li, Yuping; Veliceasa, Dorina; Kaur, Gurvinder; Ampie, Leonel; Choy, Winward; Lamano, Jason; Bloch, Orin

doi:10.1080/2162402x.2018.1448329

Cited by 94 publications

(69 citation statements)

References 44 publications

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“…PD-1 has also been implicated in the activation of epithelial-mesenchymal transition 60 and prevention of Treg expansion in glioma. 61 Estimates of PD-L1 expression on human GBM have ranged between 19% and 88%, with some variation ascribed to the technique and antibody use. [62][63][64] Prognostically, PD-1 expression on TILS and PD-L1 expression on tumor cells Open access both correlate with glioma grade.…”

Section: Ctla-4mentioning

confidence: 99%

T lymphocyte-targeted immune checkpoint modulation in glioma

Kelly

Giles

Gilbert

2020

J Immunother Cancer

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Immunomodulatory therapies targeting inhibitory checkpoint molecules have revolutionized the treatment of solid tumor malignancies. Concerns about whether systemic administration of an immune checkpoint inhibitor could impact primary brain tumors were answered with the observation of definitive responses in pediatric patients harboring hypermutated gliomas. Although initial clinical results in patients with glioblastoma (GBM) were disappointing, recently published results have demonstrated a potential survival benefit in patients with recurrent GBM treated with neoadjuvant programmed cell death protein 1 blockade. While these findings necessitate verification in subsequent studies, they support the possibility of achieving clinical meaningful immune responses in malignant primary brain tumors including GBM, a disease in dire need of additional therapeutic options. There are several challenges involved in treating glioma with immune checkpoint modulators including the immunosuppressive nature of GBM itself with high inhibitory checkpoint expression, the immunoselective blood brain barrier impairing the ability for peripheral lymphocytes to traffic to the tumor microenvironment and the high prevalence of corticosteroid use which suppress lymphocyte activation. However, by simultaneously targeting multiple costimulatory and inhibitory pathways, it may be possible to achieve an effective antitumoral immune response. To this end, there are now several novel agents targeting more recently uncovered “second generation” checkpoint molecules. Given the multiplicity of drugs being considered for combination regimens, an increased understanding of the mechanisms of action and resistance combined with more robust preclinical and early clinical testing will be needed to be able to adequately test these agents. This review summarizes our current understanding of T lymphocyte-modulating checkpoint molecules as it pertains to glioma with the hope for a renewed focus on the most promising therapeutic strategies.

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Section: Ctla-4mentioning

confidence: 99%

T lymphocyte-targeted immune checkpoint modulation in glioma

Kelly

Giles

Gilbert

2020

J Immunother Cancer

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“…Moreover, tumor-directed cytotoxic T lymphocytes function is also regulated by immune checkpoints, such as programmed death (PD-1) receptor and their ligands PD-L1 and PD-L2 ( DiDomenico et al, 2018 ). Specifically, PD-L1 is highly expressed in tumors, including gliomas.…”

Section: Microglia and Astrocytes’ Role In Glioblastoma Malignancymentioning

confidence: 99%

“…From this interaction results an inhibitory response. In this sense, increased expression of PD-L1 in GB patients has been correlated with poor survival of those receiving vaccine immunotherapy ( DiDomenico et al, 2018 ). On the other hand, GAMs also release PD-L1 and, consequently, block the T cells through PD-1/PD-L1 signaling ( Preusser et al, 2015 ).…”

Section: Microglia and Astrocytes’ Role In Glioblastoma Malignancymentioning

confidence: 99%

Microglia/Astrocytes–Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors

Matias

Balça-Silva

Graça

et al. 2018

Front. Cell. Neurosci.

137

120

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In recent years, the functions of glial cells, namely, astrocytes and microglia, have gained prominence in several diseases of the central nervous system, especially in glioblastoma (GB), the most malignant primary brain tumor that leads to poor clinical outcomes. Studies showed that microglial cells or astrocytes play a critical role in promoting GB growth. Based on the recent findings, the complex network of the interaction between microglial/astrocytes cells and GB may constitute a potential therapeutic target to overcome tumor malignancy. In the present review, we summarize the most important mechanisms and functions of the molecular factors involved in the microglia or astrocytes–GB interactions, which is particularly the alterations that occur in the cell’s extracellular matrix and the cytoskeleton. We overview the cytokines, chemokines, neurotrophic, morphogenic, metabolic factors, and non-coding RNAs actions crucial to these interactions. We have also discussed the most recent studies regarding the mechanisms of transportation and communication between microglial/astrocytes – GB cells, namely through the ABC transporters or by extracellular vesicles. Lastly, we highlight the therapeutic challenges and improvements regarding the crosstalk between these glial cells and GB.

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“…and Foxp3 expressing T cells [61][62][63][64] . BTLA activation also contributes to generation of IL10 expressing T cells 65,66 .…”

Section: Discussionmentioning

confidence: 99%

Engineered Dendritic Cell-Directed Concurrent Activation of Multiple T cell Inhibitory Pathways Induces Robust Immune Tolerance

Gudi

Karumuthil‐Melethil

Pérez

et al. 2019

Preprint

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Inhibitory/repressor-receptors are upregulated significantly on activated T cells, and have been the molecules of attention as targets for inducing immune tolerance. Induction of effective antigen specific tolerance depends on concurrent engagement of the TCR and one or more of these inhibitory receptors. Here, we show, for the first time that dendritic cells (DCs) can be efficiently engineered to express multiple T cell inhibitory ligands, and enhanced engagement of T cell inhibitory receptors, upon antigen presentation, by these DCs can induce effective CD4+ T cell tolerance and suppress autoimmunity. Compared to control DCs, antigen presentation by DCs that ectopically express CTLA4, PD1 and BTLA selective ligands (B7.1wa, PD-L1, and HVEM-CRD1 respectively) individually (mono-ligand DCs) or in combination (multi-ligand DCs) causes an inhibition of CD4+ T cell proliferation and pro-inflammatory cytokine response, as well as increase in Foxp3+ Treg frequency and immune regulatory cytokine production.Administration of self-antigen (mouse thyroglobulin; mTg) loaded multi-ligand DCs caused hyporesponsiveness to mTg challenge, suppression of autoantibody production, and amelioration of experimental autoimmune thyroiditis. Overall, this study shows that engineered DC-directed enhanced concurrent activation of multiple T cell coinhibitory pathways is an effective way to induce self-antigen specific T cell tolerance to suppress ongoing autoimmunity.

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The immune checkpoint protein PD-L1 induces and maintains regulatory T cells in glioblastoma

Cited by 94 publications

References 44 publications

T lymphocyte-targeted immune checkpoint modulation in glioma

T lymphocyte-targeted immune checkpoint modulation in glioma

Microglia/Astrocytes–Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors

Engineered Dendritic Cell-Directed Concurrent Activation of Multiple T cell Inhibitory Pathways Induces Robust Immune Tolerance

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