ABSTRACT Glioblastoma (GBM), the most common primary malignant brain tumor, is among the most lethal of cancers. It is also among the most immunosuppressive, impeding the success of immune-based therapies. The tumor has an especially devastating impact on T cells, which either vanish from the blood and lymphoid organs or persist in a state of pronounced dysfunction. While T cell dysfunction has been well characterized, their disappearance has not, instead remaining a mystery for decades. Our novel data reveal that the missing T cells are frequently found in large numbers in the bone marrow. This proves true in both patients and mice with GBM, each of which harbor a 3 to 5-fold expansion in bone marrow T cell counts. Such expansion contrasts starkly with observations of AIDS-level CD4 T cell counts in blood and gross contraction of other lymphoid organs, including the spleen. Sequestration in bone marrow is suggested as T cells transferred into GBM- bearing mice accumulate in the marrow disproportionately over the ensuing 24 hours. Furthermore, when marrow-sequestered T cells from GBM-bearing mice are transferred back into controls, they preferentially re- accumulate in the bone marrow, suggesting T cells acquire alterations eliciting their sequestration. Notably, these phenomena are observed when other cancers are implanted intracranially, but never when the same tumors are placed subcutaneously, including GBM. This implies a unique role for the brain environment in mediating the T cell sequestration. Our preliminary studies suggest that T cells become sequestered in bone marrow in the GBM-bearing state as a result of diminished levels of T cell surface sphingosine-1-phosphate receptor 1 (S1P1). We propose to: 1) further define the role of S1P1 in mediating bone marrow T cell sequestration in GBM; 2) delineate the upstream determinants of S1P1 downregulation in the tumor-bearing state; and 3) devise means of reversing T cell sequestration, with the ultimate goals of replenishing the missing peripheral T cell pool and improving the efficacy of immune-based GBM therapies.