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.
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.
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.
Other team members: Craig Horbinski
Medulloblastomas comprise the vast majority of pediatric embryonal tumors and by definition arise in the posterior fossa, where they constitute approximately 40% of all posterior fossa tumors. Other forms of embryonal tumors each make up 2% or less of all childhood brain tumors.The clinica
High-grade glioma/astrocytoma (WHO grade III/IV)
High-grade Gliomas (HGG) in children nearly always result in a dismal prognosis. Although novel therapeutic approaches are currently in development, preclinical testing has been limited, due to a lack of pediatric specific HGG preclinical models. These models are needed to help test the effective
Low-Grade astrocytomas are the most common cancer of the central nervous system in children. They represent a heterogeneous group of tumors that can be discovered anywhere within the brain or spinal cord. Although surgical resection may be curative, up to 20% of children still suffer from the eff
Ependymomas arise from ependymal cells that line the ventricles and passageways in the brain and the center of the spinal cord. Ependymal cells produce cerebrospinal fluid (CSF). These tumors are classified as supratentorial or infratentorial. In children, most ependymomas are infratentorial tumo
Brainstem glioma- Diffuse intrinsic pontine glioma
A presumptive diagnosis of DIPG based on classic imaging features, in the absence of a histologic diagnosis, has been routinely employed. Increasingly however, histologic confirmation is obtained for both entry into research studies and molecular characterization of the tumor.[
Immunotherapeutically-targeting IDO1 in pediatric high-grade glioma
Patients diagnosed with high-grade pediatric brain tumors have long-term survival rates of only 10 - 15% despite aggressive treatments with surgery and irradiation. To address this grim prognosis, cancer immunotherapy, a strategy whereby the host immune system is re-targeted/reactivated to cause
PDTM-10. Novel RNA-Targeting Strategy for Treating T Cell-Driven Immunosuppression in Human Diffuse Intrinsic Pontine Glioma
PURPOSE: Our laboratory’s work in adult high-grade glioma has discovered, a therapeutically-targetable pathway through the inducible expression of indoleamine 2,3 dioxygenase 1 (IDO1). IDO1 is an immunosuppressive enzyme that metabolizes tryptophan (Trp). The premise of our project is to delineat
Alicia Lenzen, Kristen Lauing, Lijie Zhai, Erik Ladomersky, Pichai Raman, Komal Rathi, Rishi Lulla, Rintaro Hashizume, Derek Wainwright