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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow / immunology*
  • Brain Neoplasms / immunology*
  • Brain Neoplasms / pathology
  • Endocytosis
  • Glioblastoma / immunology*
  • Glioblastoma / pathology
  • Humans
  • Lymphoid Tissue / pathology
  • Lymphopenia / immunology
  • Lysophospholipids / metabolism
  • Mice, Inbred C57BL
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Spleen / pathology
  • T-Lymphocytes / immunology*

Substances

  • Lysophospholipids
  • sphingosine 1-phosphate
  • Sphingosine