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

Nature Medicine volume 24, pages 1459–1468 (2018)Cite this article

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An Author Correction to this article was published on 22 January 2019

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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.

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Fig. 1: T cell lymphopenia and splenic contraction in treatment-naïve subjects with GBM.
Fig. 2: Recapitulated T cell lymphopenia and lymphoid organ contraction in murine glioma.
Fig. 3: Naïve T cells accumulate in the bone marrow of mice and subjects with GBM.
Fig. 4: T cell accumulation in bone marrow reflects intracranial tumor location rather than tumor histologic type.
Fig. 5: Loss of surface S1P1 on T cells directs their sequestration in bone marrow in the setting of intracranial tumors.
Fig. 6: Hindering S1P1 internalization abrogates T cell sequestration in bone marrow.

Change history

  • 22 January 2019

    In the version of this article originally published, the figure callout in this sentence was incorrect: “Furthermore, in S1P1-KI mice themselves, whereas PD-1 blockade was ineffectual as monotherapy, the effects of 4-1BB agonism and checkpoint blockade proved additive, with the combination prolonging median survival and producing a 50% long-term survival rate (Fig. 6f).” The callout should have been to Supplementary Fig. 6b. The error has been corrected in the PDF and HTML versions of the article.

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Acknowledgements

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.

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Author notes

  1. These authors contributed equally: P. Chongsathidkiet, C. Jackson, S. Koyama.

Authors and Affiliations

  1. Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

    Pakawat Chongsathidkiet, Xiuyu Cui, S. Harrison Farber, Karolina Woroniecka, Aladine A. Elsamadicy, Cosette A. Dechant, Hanna R. Kemeny, Luis Sanchez-Perez, John H. Sampson & Peter E. Fecci

  2. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA

    Pakawat Chongsathidkiet, Xiuyu Cui, S. Harrison Farber, Karolina Woroniecka, Aladine A. Elsamadicy, Cosette A. Dechant, Hanna R. Kemeny, Luis Sanchez-Perez, John H. Sampson & Peter E. Fecci

  3. Department of Pathology, Duke University Medical Center, Durham, NC, USA

    Pakawat Chongsathidkiet, Karolina Woroniecka, Jeffrey I. Everitt, John H. Sampson, Michael D. Gunn & Peter E. Fecci

  4. Department of Neurosurgery, The John Hopkins University School of Medicine, Baltimore, MD, USA

    Christina Jackson

  5. Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita City, Osaka, Japan

    Shohei Koyama

  6. Department of Neurosurgery, Charité Medical University, Berlin, Germany

    Franziska Loebel

  7. Department of Neurosurgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA

    S. Harrison Farber

  8. Unum Therapeutics, Cambridge, MA, USA

    Tooba A. Cheema

  9. Dana–Farber Cancer Institute, Boston, MA, USA

    Nicholas C. Souders

  10. Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA

    James E. Herndon

  11. Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Jean-Valery Coumans, Brian V. Nahed, Robert L. Martuza & William T. Curry

  12. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA

    John H. Sampson

  13. Department of Immunology, Duke University Medical Center, Durham, NC, USA

    John H. Sampson & Michael D. Gunn

  14. Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA

    Michael D. Gunn

  15. Novartis Institutes for Biomedical Research, Cambridge, MA, USA

    Glenn Dranoff

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Contributions

P.C., C.J., S.K., F.L., N.C.S., J.-V.C., B.V.N., and P.E.F. obtained and/or analyzed human data. P.C., C.J., S.K., X.C., S.H.F., K.W., A.A.E., C.A.D., H.R.K., L.S.-P., T.A.C., and P.E.F. designed, carried out, and/or analyzed in vitro and in vivo animal experiments. J.I.E. provided pathological characterization and immunohistochemistry analyses. J.E.H. provided biostatistics consultation. J.H.S., M.D.G., R.L.M., G.D., W.T.C., and P.E.F. provided feedback and supervised all research. P.C., C.A.D., and P.E.F. wrote the manuscript. All authors read, revised, and approved the final manuscript.

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Correspondence to Peter E. Fecci.

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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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