Format

Send to

Choose Destination
Nat Med. 2018 Sep;24(9):1459-1468. doi: 10.1038/s41591-018-0135-2. Epub 2018 Aug 13.

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

Author information

1
Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.
2
Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.
3
Department of Pathology, Duke University Medical Center, Durham, NC, USA.
4
Department of Neurosurgery, The John Hopkins University School of Medicine, Baltimore, MD, 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, AZ, USA.
8
Unum Therapeutics, Cambridge, MA, USA.
9
Dana-Farber Cancer Institute, Boston, MA, USA.
10
Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.
11
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
12
Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
13
Department of Immunology, Duke University Medical Center, Durham, NC, USA.
14
Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
15
Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
16
Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. peter.fecci@duke.edu.
17
Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. peter.fecci@duke.edu.
18
Department of Pathology, Duke University Medical Center, Durham, NC, USA. peter.fecci@duke.edu.

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 subjects 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.

PMID:
30104766
PMCID:
PMC6129206
[Available on 2019-02-13]
DOI:
10.1038/s41591-018-0135-2

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center