Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors.
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.
Chongsathidkiet, P; Jackson, C; Koyama, S; Loebel, F; Cui, X; Farber, SH; Woroniecka, K; Elsamadicy, AA; Dechant, CA; Kemeny, HR; Sanchez-Perez, L; Cheema, TA; Souders, NC; Herndon, JE; Coumans, J-V; Everitt, JI; Nahed, BV; Sampson, JH; Gunn, MD; Martuza, RL; Dranoff, G; Curry, WT; Fecci, PE
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