# IDO1 and Immunotolerance in Glioblastoma

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $406,136

## Abstract

ABSTRACT
Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumor in adults. Median
survival for GBM patients is 14.6 months post-diagnosis. A consistent feature of GBM is the intratumoral
presence of immunosuppressive regulatory T cells (Treg) that impair patient anti-GBM immune response,
coincident with the expression of 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, I 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 prompted the investigation into pharmacologic inhibition
of IDO1 as a means to therapeutically induce anti-GBM immunity. Surprisingly, however, the administration of
IDO1 inhibitor had no effect on intratumoral Treg accumulation nor on animal subject survival. A hypothesis that
provides an explanation for this paradox, addressing how genetic suppression-, but not pharmacologic inhibition-
of IDO1, affects intratumoral Treg accumulation and effector T cell response against GBM, forms the basis of
this proposal. Recently, my lab discovered that cells in the tumor microenvironment, but not GBM cells, are
responsible for nearly all IDO1-mediated Trp to Kyn catabolism in the GL261-C57BL6 model. This observation,
however, raises a question regarding the role of tumor cell-associated IDO1, whose genetic suppression
promotes productive T cell response against tumor. A potential answer to this question has emerged in
association with our discovery that IDO1 localizes to the nucleus in GBM cells. Based on these observations we
propose to: 1) establish IDO1 cell type expression and catabolism in human GBM in situ, 2) investigate IDO1
expression and function in human GBM cells and to 3) determine the function of nuclear IDO1 in GBM cells. The
proposed studies aim to investigate clinically-relevant questions and approaches that aim to reverse
immunosuppression in glioma, which is the first step to the rational design of effective immunotherapy for patients
with incurable brain cancer.

## Key facts

- **NIH application ID:** 9975916
- **Project number:** 5R01NS097851-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Derek Alan Wainwright
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $406,136
- **Award type:** 5
- **Project period:** 2016-08-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975916

## Citation

> US National Institutes of Health, RePORTER application 9975916, IDO1 and Immunotolerance in Glioblastoma (5R01NS097851-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9975916. Licensed CC0.

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