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- W2588797826 abstract "Glioblastoma (GBM), the most common and universally lethal primary brain tumor, is amongst the most immunosuppressive of solid tumors. Despite rarely metastasizing outside the CNS, GBM elicits profound T-cell lymphopenia and systemic T-cell dysfunction. Lymphopenia in GBM patients is frequently attributed to therapies incorporating temozolomide, dexamethasone, and radiation. We reveal, however, that even treatment-naïve patients frequently demonstrate dramatically diminished T-cell counts, including AIDS-level CD4 counts of 200 cells/μL or below. Patients simultaneously exhibit lymphoid organs retraction, averaging a 30% reduction in spleen volume. While disappearing from these compartments, T-cells instead re-appear in large numbers in the bone marrow. Patients can harbor up to 20-fold higher T-cell counts in marrow compared to blood. These findings are recapitulated in murine GBM models, where spleens and thymuses contract severely in size, while marrow T-cell counts increase 3 to 5-fold. Adoptive transfer experiments suggest that T-cells are sequestered in marrow after acquiring alterations in the intracranial tumor-bearing state. We uncover the requisite T-cell alteration to be downregulation of surface sphingosine-1-phosphate receptor type 1 (S1P1). Pharmacologically induced S1P1 loss on T-cells is sufficient to elicit their immediate sequestration in GBM-bearing mice, while genetic stabilization of the receptor abrogates the phenomenon. These findings characterize not only GBM, but various other malignancies (lung, melanoma, breast), yet only when these tumors are implanted intracranially. Importantly, abrogating sequestration alone conveys a survival benefit in murine GBM with accompanying increased numbers of activated tumor-infiltrating lymphocytes. We, therefore, advance here a novel mode of T-cell dysfunction in cancer contributed specifically by the intracranial environment: S1P1-mediated bone marrow T-cell sequestration. This finding likewise suggests that the brain harbors unique mechanisms for preventing T cell entry into the CNS, mechanisms which are usurped by tumors to favor immune escape. More broadly, such mechanisms are anticipated to hold numerous implications for basic CNS immunology." @default.
- W2588797826 created "2017-02-24" @default.
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- W2588797826 date "2016-11-01" @default.
- W2588797826 modified "2023-10-16" @default.
- W2588797826 title "IMST-11. DOWNREGULATION OF SPHINGOSINE-1-PHOSPHATE RECEPTOR TYPE 1 MEDIATES BONE MARROW T-CELL SEQUESTRATION IN PATIENTS AND MICE WITH GLIOBLASTOMA" @default.
- W2588797826 doi "https://doi.org/10.1093/neuonc/now212.367" @default.
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