PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer

Diskin, Brian; Adam, Salma; Cassini, Marcelo Ferreira; Sanchez, Gustavo; Liria, Miguel; Aykut, Berk; Buttar, Chandan; Li, Eric; Sundberg, Belen; Salas, Ruben D.; Chen, Ruonan; Wang, Junjie; Kim, Mirhee; Farooq, Mohammad Saad; Nguy, Susanna; Fedele, Carmine; Tang, Kwan Ho; Chen, Ting; Wang, Wei; Hundeyin, Mautin; Rossi, Juan Andres Kochen; Kurz, Emma; Haq, Muhammad Israr Ul; Karlen, Jason; Kruger, Emma; Sekendiz, Zennur; Wu, Dongling; Shadaloey, Sorin A. A.; Baptiste, Gillian; Werba, Gregor; Selvaraj, Shanmugapriya; Loomis, Cynthia A.; Wong, Kwok-Kin; Leinwand, Joshua; Miller, George

doi:10.1038/s41590-020-0620-x

Cited by 292 publications

(261 citation statements)

References 44 publications

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“…Yet, new evidence has uncovered some unexpected twists in the PD-1/PD-L1 biology that need to be considered when analyzing the potential outcomes of treatment or predictive value of PD-L1 expression in certain patient cohorts. A protective role of PD-L1 expressed on T-cells [ 27 ], the discovery of PD-L1 bidirectional signaling in T-cells [ 29 ] and PD-L1-mediated sequestration of T-cell activation signals on dendritic cells [ 17 ] indicate non-redundant roles for PD-1 and PD-L1 blockade and the potential for combination therapies. PD-1 expression on macrophages [ 46 ] and tumor cells [ 179 ] identifies these cell types as direct targets of PD-1 blockade and indicates the potential for unexpected treatment outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…The ligation of PD-L1 expressed by T-cells can promote tumor immune escape via diverse mechanisms [ 29 ]. First, T-cell-expressed PD-L1 can engage with PD-1 expressed on macrophages to promote M2 polarization.…”

Section: Pd-l1 Expression On Non-tumor Cellsmentioning

confidence: 99%

“…Third, T-cell-expressed PD-L1 can function as a receptor in T-cells. This so-called “back-signaling” can promote T-helper 1 (Th1)-to-Th17 switch in CD4 T-cells [ 29 ], a non-responsive (anergic) phenotype in CD8 T-cells [ 29 ] and apoptosis in activated T-cells [ 30 ]; the ligation of PD-L1 on T-cells was as efficient as PD-1 ligation in suppressing T-cell functionality [ 29 ]. In addition to PD-1 and PD-L1, activated T-cells can also express CD80 known to restrain T-cell effector function through CTLA-4 [ 31 ]; the role for PD-L1–CD80 interactions in T-cell bidirectional signaling remains to be addressed.…”

Section: Pd-l1 Expression On Non-tumor Cellsmentioning

confidence: 99%

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Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

Shklovskaya

Rizos

2020

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Pd-l1 Expression On Non-tumor Cellsmentioning

confidence: 99%

Section: Pd-l1 Expression On Non-tumor Cellsmentioning

confidence: 99%

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Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

Shklovskaya

Rizos

2020

IJMS

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“…Inhibition of STAT3 by PD-L1 intrinsic signaling ensures the abrogation of interferon-mediated apoptosis (Gato-Canas et al, 2017), stimulates the inflammasome pathway in cancer cells (Theivanthiran et al, 2020), and directly inhibits PD-L1-positive T cells (Diskin et al, 2020). PD-L1-regulated inflammasome activation triggers a series of signaling cascades that end up with the recruitment of granulocyte myeloid-derived suppressor cells (MDSC) in the tumor environment.…”

Section: Tumor-intrinsic Factors and Resistance To Pd-l1/pd-1 Blockadmentioning

confidence: 99%

Resistance to PD-L1/PD-1 Blockade Immunotherapy. A Tumor-Intrinsic or Tumor-Extrinsic Phenomenon?

et al. 2020

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Cancer immunotherapies targeting immune checkpoints such as programmed cell-death protein 1 (PD-1) and its ligand programmed cell-death 1 ligand 1 (PD-L1), are revolutionizing cancer treatment and transforming the practice of medical oncology. However, despite all the recent successes of this type of immunotherapies, most patients are still refractory and present either intrinsic resistance or acquired resistance. Either way, this is a major clinical problem and one of the most significant challenges in oncology. Therefore, the identification of biomarkers to predict clinical responses or for patient stratification by probability of response has become a clinical necessity. However, the mechanisms leading to PD-L1/PD-1 blockade resistance are still poorly understood. A deeper understanding of the basic mechanisms underlying resistance to cancer immunotherapies will provide insight for further development of novel strategies designed to overcome resistance and treatment failure. Here we discuss some of the major molecular mechanisms of resistance to PD-L1/PD-1 immune checkpoint blockade and argue whether tumor intrinsic or extrinsic factors constitute main determinants of response and resistance.

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“…PD-L1 is expressed on activated T cells and is required for T cell conditioning and dendritic cell maturation 60 . However, its expression on T cells has been mostly linked to inhibition of their responses 61,62 . Other studies indicates that expression of PD-L1 on CD8 + and CD4 + T cells correlates with patient response to ICB, suggesting PD-L1 expression in CD8 + T cells as a prognostic marker in melanoma 12,63,64 .…”

Section: Usp18 Regulates Mhc Class I Antigen Presentation Pd-l1 Exprmentioning

confidence: 99%

Deep analysis of the USP18-dependent ISGylome and proteome unveils important roles for USP18 in tumour cell antigenicity and radiosensitivity

Pinto-Fernández

Salio

Partridge

et al. 2020

Preprint

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words)The deubiquitylating enzyme USP18 is a major negative regulator of the interferon (IFN) signalling cascade. IFN pathways contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy and are often deregulated in cancer. USP18 is the predominant human protease that cleaves interferon-stimulated gene ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteins in vivo. In this study, using advanced proteomic techniques, we have expanded the USP18dependent ISGylome and proteome in a chronic myeloid leukaemia (CML)-derived cell line (HAP1) treated with type I IFN. Novel ISGylation targets were characterised that modulate the sensing of innate ligands, antigen presentation and secretion of cytokines. Consequently, CML USP18-deficient cells are more antigenic, driving increased activation of cytotoxic T lymphocytes (CTLs) and are more susceptible to irradiation. Our results suggest USP18 as a pharmacological target in cancer immunotherapy and radiotherapy.

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PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer

Cited by 292 publications

References 44 publications

Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

Resistance to PD-L1/PD-1 Blockade Immunotherapy. A Tumor-Intrinsic or Tumor-Extrinsic Phenomenon?

Deep analysis of the USP18-dependent ISGylome and proteome unveils important roles for USP18 in tumour cell antigenicity and radiosensitivity

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