Exploration of IDO1 as a therapeutic target in pediatric central nervous system tumors

Email Principal Investigator
Completed
Specimen
Medulloblastoma
HGG
LGG
Ependymoma
DIPG
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Rishi Ramesh Lulla

CBTN Samples Used

45

CBTN Participants

45

CBTN Samples

Backer

NIH

Neuro-Oncology Research Fund at Lurie Children's Hospital.

Completed

About this

Project

Because the immune system can suppress and even eradicate tumor growth, tumor progression in central nervous system (CNS) tumors has been linked to immune evasion strategies. The capability of the immune system to recognize and inhibit the growth of cancer is dependent on its ability to recognize the variety of genetic and epigenetic variations that characterize tumors. Immune system function and tumor suppression further relies on the complex interplay between stimulatory and inhibitory signals present on the tumor, tumor microenvironment and immune effector cells. The phenomenon has been well studied in some models of CNS tumors.

A consistent feature of adult glioblastoma is the intratumoral presence of immunosuppressive regulatory T cells (Treg) that impair patient anti-GBM immune response and the expression indoleamine 2,3 dioxygenase 1 (IDO1), a rate-limiting enzyme that converts tryptophan (Trp) to kynurenine (Kyn). Utilizing the orthotopic, syngeneic and immunocompetent GL261-C57BL6 engraftment model, Waingwright et. al. have previously demonstrated that shRNA-mediated suppression of IDO1 expression in murine GBM cells significantly decreases intratumoral Treg accumulation coincident with a cytolytic T cell response leading to complete tumor regression. This observation is coincident with the clinical finding that, overall survival is decreased in adult patients with upregulated IDO1 mRNA expression in glioma, when compared to intermediately- and downregulated-expressing specimens. This has been further validated at the protein level. Collectively, these data suggest that IDO1 is a high value target for immunotherapeutic consideration in adult glioma. However, whether these findings translate to pediatric brain tumors has yet to be explored. This proposal aims to determine the level of IDO1 expression in pediatric CNS tumors, specifically focus on low grade glioma, high grade glioma, medulloblastoma and ependymoma.

Ask The

Scientists

Ask the scientists

What are the goals of this project?

We propose to obtain expression levels of IDO1 mRNA and DNA will be used to confirm for whole exome and methylation profiling.

What is the impact of this project?

We are investigating IDO1 expression in pediatric CNS Tumors to continue to expand the potential therapeutic targets for immune mediated therapies.

Specimen Data

The Children's Brain Tumor Network contributed 16 high-grade glioma samples, 20 low-grade glioma samples, 20 medulloblastoma samples, 18 ependymoma samples and 12 DIPG samples to this project.

related

Histologies