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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS099096-02
Application #
9394042
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
2016-12-15
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Duke University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705