Intracranial Tumors Lead To Sequestration Of T Cells In The Bone Marrow

Abstract Glioblastoma (GBM) is the most common primary, malignant brain tumor and is universally fatal. Immunotherapeutic intervention has shown some success in immunogenic solid tumors, but little efficacy in GBM. Tumor-imposed T cell deficits remain a major obstacle. Recently, we demonstrated that GBM patients exhibit local and systemic T cell dysfunction, severe lymphopenia and contracted lymphoid organs. These observations are recapitulated in multiple murine models of GBM. Although T cell numbers are decreased in blood, lymph nodes, and spleen, we find large numbers of T cells sequestered in the bone marrow of both patients and mice with GBM. T cell sequestration occurs not only in the setting of GBM, but with nearly any cancer placed intracranially. Intriguingly, none of the tumors tested, including GBM, induce sequestration of T cells in the bone marrow when implanted subcutaneously. These data suggest that the capacity to sequester T cells resides within the brain and is usurped by tumors of the intracranial compartment. Such capacities may well represent a novel mechanism of immune privilege. Sequestration of T cells follows loss of sphingosine-1 phosphate-receptor 1 (S1P1) from the T cell surface. Understanding the drivers of S1P1 loss will provide crucial insight for how brain tumors facilitate systemic immune alterations and permit the development of more effective immune-based strategies for brain tumor patients.