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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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.

Author information

Author notes

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

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.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Peter E. Fecci.

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https://doi.org/10.1038/s41591-018-0135-2

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