61
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Sequestration of T-cells in bone marrow in the setting of glioblastoma and other intracranial tumors

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          T-cell dysfunction contributes to tumor immune escape in patients with cancer and is particularly severe amidst glioblastoma (GBM). Among other defects, T-cell lymphopenia is characteristic, yet often attributed to treatment. We reveal that even treatment-naïve patients and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T-cell deficient lymphoid organs. Missing naïve T-cells are instead found sequestered in large numbers in the bone marrow. This phenomenon characterizes not only GBM but a variety of other cancers, although only when tumors are introduced into the intracranial compartment. T-cell sequestration is accompanied by tumor-imposed loss of S1P1 from the T-cell surface and is reversible upon precluding S1P1 internalization. In murine models of GBM, hindering S1P1 internalization and reversing sequestration licenses T-cell-activating therapies that were previously ineffective. Sequestration of T-cells in bone marrow is therefore a tumor-adaptive mode of T-cell dysfunction, whose reversal may constitute a promising immunotherapeutic adjunct.

          Related collections

          Most cited references36

          • Record: found
          • Abstract: found
          • Article: not found

          Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

          Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Sphingosine-1-phosphate: an enigmatic signalling lipid.

            The evolutionarily conserved actions of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), in yeast, plants and mammals have shown that it has important functions. In higher eukaryotes, S1P is the ligand for a family of five G-protein-coupled receptors. These S1P receptors are differentially expressed, coupled to various G proteins, and regulate angiogenesis, vascular maturation, cardiac development and immunity, and are important for directed cell movement.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Tolerance and exhaustion: defining mechanisms of T cell dysfunction.

              CD8 T cell activation and differentiation are tightly controlled, and dependent on the context in which naïve T cells encounter antigen, can either result in functional memory or T cell dysfunction, including exhaustion, tolerance, anergy, or senescence. With the identification of phenotypic and functional traits shared in different settings of T cell dysfunction, distinctions between such dysfunctional states have become blurred. Here, we discuss distinct states of CD8 T cell dysfunction, with an emphasis on: (i) T cell tolerance to self-antigens (self-tolerance); (ii) T cell exhaustion during chronic infections; and (iii) tumor-induced T cell dysfunction. We highlight recent findings on cellular and molecular characteristics defining these states, cell-intrinsic regulatory mechanisms that induce and maintain them, and strategies that can lead to their reversal. Copyright © 2013 Elsevier Ltd. All rights reserved.
                Bookmark

                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                30 June 2018
                13 August 2018
                September 2018
                13 February 2019
                : 24
                : 9
                : 1459-1468
                Affiliations
                [1 ]Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA
                [2 ]Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA
                [3 ]Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA
                [4 ]Department of Neurosurgery, the John Hopkins University School of Medicine, Baltimore, Maryland, USA
                [5 ]Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita City, Osaka, Japan
                [6 ]Department of Neurosurgery, Charité Medical University, Berlin, Germany
                [7 ]Department of Neurosurgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, USA
                [8 ]Unum Therapeutics, Cambridge, Massachusetts, USA
                [9 ]Dana-Farber Cancer Institute, Boston, Massachusetts, USA
                [10 ]Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, USA
                [11 ]Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
                [12 ]Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA
                [13 ]Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA
                [14 ]Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
                [15 ]Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA
                Author notes
                [* ]Corresponding author: Peter E. Fecci. peter.fecci@ 123456duke.edu
                [16]

                These authors contributed equally: Pakawat Chongsathidkiet, Christina Jackson, Shohei Koyama.

                Article
                NIHMS978402
                10.1038/s41591-018-0135-2
                6129206
                30104766
                8f0e86a8-43aa-4347-907f-7ec99e8b1dbe

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Categories
                Article

                Medicine
                Medicine

                Comments

                Comment on this article