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.
Glioblastoma (GBM), the most common primary malignant brain tumor, is among the most lethal of cancers. It is also among the most immunosuppressive, severely impeding T cells and the success of immune-based therapies. While patients and mice with GBM demonstrate profound T cell lymphopenia and associated lymphoid organ contraction, we have uncovered that T cells are instead frequently found in large numbers in the bone marrow. This proposal focuses on a mechanistic examination of T cell sequestration in the bone marrow of patients and mice with glioblastoma, as well as methods to release these trapped T cells to enhance tumor-targeted immunotherapy.
|Chongsathidkiet, Pakawat; Jackson, Christina; Koyama, Shohei et al. (2018) Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med 24:1459-1468|
|Woroniecka, Karolina I; Rhodin, Kristen E; Chongsathidkiet, Pakawat et al. (2018) T-cell Dysfunction in Glioblastoma: Applying a New Framework. Clin Cancer Res 24:3792-3802|