# Thymic PD-1 blockade mediates the anti-tumor immune response in pediatric high-grade glioma

> **NIH NIH F30** · UNIVERSITY OF FLORIDA · 2022 · $41,749

## Abstract

Project Summary/Abstract
Programmed cell death 1 (PD-1) and its ligands, PD-L1 and PD-L2, are highly expressed in human and murine
thymus. Despite this knowledge, the function of the PD-1 signaling pathway during T cell development has been
severely understudied. In the past decade, immunotherapies inhibiting the PD-1:PD-L1 axis have produced
remarkable improvements in the clinical management of several malignancies, at least in part by restoring T cell
receptor (TCR) signaling within the immunosuppressive tumor microenvironment. However, because TCR
signaling is essential for thymocyte development, we postulate PD-1/PD-L1 inhibitors may have profound effects
on the function and specificity of newly generated T cells. These thymus-specific actions may highlight a key
unexplored mechanism by which PD-1 blockade elicits anti-tumor immune responses. Leveraging this pathway
for pediatric cancer patients may be particularly beneficial considering their high rate of thymic T cell production.
Our preliminary data illustrate that hematopoietic stem cells (HSCs) administered in conjunction with anti-PD-1
therapy expands the T cell pool and helps overcome treatment-resistance in murine glioblastoma. This may
suggest anti-PD-1 therapy acts within the thymus to promote the proliferation and maturation of HSC-derived
thymocytes. Importantly, pediatric high-grade glioma (HGG) is the prevailing cause of cancer-related death in
children which emphasizes the need for new therapies. Thus it is our priority to investigate this novel pathway
with the goal of improving the standard of care for pediatric HGG and other childhood tumors. Our objective is
to characterize how inhibiting PD-1 signaling modifies thymocyte development in health and HGG. The central
hypothesis of this proposal is that PD-1 inhibition increases thymic T cell production and promotes the positive
selection, or survival, of tumor-specific TCRs. Aim 1 will determine the impact of PD-1 blockade on the
proliferation, selection, and output of developing thymocytes in healthy and glioma-bearing mice. Aim 2 will
assess the thymic contribution towards the therapeutic response in the context of PD-1 inhibiton and HSC
transfer. This work is significant because no prior study has investigated how thymus-specific PD-1 blockade
impacts anti-tumor immune responses. The results from this study have the potential to substantially influence
clinical decision making and treatment regimens for pediatric HGG patients. This project is innovative because
it will utilize nontransgenic mouse models to more accurately define how PD-1 inhibition affects thymus
physiology in health and disease. In summary this proposal will comprehensively characterize how the PD-1
pathway modulates T cell development and will investigate a novel thymic mechanism that may revolutionize
our understanding of anti-PD-1 therapy in cancer.

## Key facts

- **NIH application ID:** 10413861
- **Project number:** 5F30CA260911-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Connor Patrick Francis
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $41,749
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413861

## Citation

> US National Institutes of Health, RePORTER application 10413861, Thymic PD-1 blockade mediates the anti-tumor immune response in pediatric high-grade glioma (5F30CA260911-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10413861. Licensed CC0.

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