Chongsathidkiet et al. found that treatment-naive patients and mice with glioblastoma have severely reduced naive T cell counts in the blood. Surprisingly, these cells were not sequestered in the spleen or thymus (both organs were contracted), but instead accumulated in the bone marrow (BM). This was also observed with other cancer types in mice, but only if the tumors were introduced intracranially. Sequestration of T cells in the BM was due to the loss of S1P1 on their surface, and was reversible when S1P1 internalization was blocked. Releasing the T cells from the BM enabled previously ineffective immunotherapies to improve survival in mice.
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-naive subjects and mice with GBM can harbor AIDS-level CD4 counts, as well as contracted, T cell-deficient lymphoid organs. Missing naive 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.
Author Info: (1) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. Departmen
Author Info: (1) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. Department of Pathology, Duke University Medical Center, Durham, NC, USA. (2) Department of Neurosurgery, The John Hopkins University School of Medicine, Baltimore, MD, USA. (3) Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita City, Osaka, Japan. (4) Department of Neurosurgery, Charite Medical University, Berlin, Germany. (5) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. (6) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA. (7) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. Department of Pathology, Duke University Medical Center, Durham, NC, USA. (8) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. (9) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. (10) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. (11) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. (12) Unum Therapeutics, Cambridge, MA, USA. (13) Dana-Farber Cancer Institute, Boston, MA, USA. (14) Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA. (15) Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (16) Department of Pathology, Duke University Medical Center, Durham, NC, USA. (17) Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (18) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. Department of Pathology, Duke University Medical Center, Durham, NC, USA. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA. Department of Immunology, Duke University Medical Center, Durham, NC, USA. (19) Department of Pathology, Duke University Medical Center, Durham, NC, USA. Department of Immunology, Duke University Medical Center, Durham, NC, USA. Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA. (20) Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (21) Novartis Institutes for Biomedical Research, Cambridge, MA, USA. (22) Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (23) Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA. peter.fecci@duke.edu. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. peter.fecci@duke.edu. Department of Pathology, Duke University Medical Center, Durham, NC, USA. peter.fecci@duke.edu.
