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

• Published in: Nature medicine Vol. 24; no. 9; pp. 1459 - 1468
• Main Authors: Chongsathidkiet, Pakawat, Jackson, Christina, Koyama, Shohei, Loebel, Franziska, Cui, Xiuyu, Farber, S Harrison, Woroniecka, Karolina, Elsamadicy, Aladine A, Dechant, Cosette A, Kemeny, Hanna R, Sanchez-Perez, Luis, Cheema, Tooba A, Souders, Nicholas C, Herndon, James E, Coumans, Jean-Valery, Everitt, Jeffrey I, Nahed, Brian V, Sampson, John H, Gunn, Michael D, Martuza, Robert L, Dranoff, Glenn, Curry, William T, Fecci, Peter E
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.09.2018
• Subjects: Acquired immune deficiency syndrome; AIDS; Animal models; Animals; Bone marrow; Bone Marrow - immunology; Bone tumors; Brain cancer; Brain Neoplasms - immunology; Brain Neoplasms - pathology; Cancer; CD4 antigen; Cell surface; Endocytosis; Glioblastoma; Glioblastoma - immunology; Glioblastoma - pathology; Humans; Internalization; Licenses; Lymphocytes; Lymphocytes T; Lymphoid Tissue - pathology; Lymphopenia; Lymphopenia - immunology; Lysophospholipids - metabolism; Mice, Inbred C57BL; Organs; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Spleen - pathology; T-Lymphocytes - immunology; Tumors
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-018-0135-2

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.