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.
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We would like to thank G.E. Archer, K.A. Batich, T.A. Chewning, K.L. Congdon, K.A. Keith, R.J. Lefkowitz, P.K. Norberg, E.A. Reap, L.A.M. Rein, K.E. Rhodin, A. Seas, S.H. Shen, R.J. Schmittling, D.J. Snyder, C.M. Suryadevara, A.M. Swartz, W.H. Tomaszewski, D.S. Wilkinson, W. Xie, H. Yang, and members of the Duke Brain Tumor Immunotherapy Program for their insights throughout the study. We would like to thank M. Foster and J.W. Thompson from the Proteomics and Metabolomics Shared Resource, Duke Center for Genomic and Computational Biology for help with liquid chromatography-tandem mass spectrometry analyses. We would like to thank M.R. Llewellyn for the preparation of medical illustrations. This work was supported by institutional start-up funds from Duke University Medical Center, The Sontag Foundation Distinguished Scientist Award, and the National Institutes of Health R01NS099096 to P.E.F.
The authors declare no competing interests.
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Chongsathidkiet, P., Jackson, C., Koyama, S. et al. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med 24, 1459–1468 (2018). https://doi.org/10.1038/s41591-018-0135-2
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