# A Novel Clinical Challenge in Brain Tumor Immunology: T cell Sequestration

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $331,118

## Abstract

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.

## Key facts

- **NIH application ID:** 9824588
- **Project number:** 5R01NS099096-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Peter Fecci
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $331,118
- **Award type:** 5
- **Project period:** 2016-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9824588

## Citation

> US National Institutes of Health, RePORTER application 9824588, A Novel Clinical Challenge in Brain Tumor Immunology: T cell Sequestration (5R01NS099096-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9824588. Licensed CC0.

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