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IDO1 and Immunotolerance in Glioblastoma

IDO1 和胶质母细胞瘤的免疫耐受

基本信息

批准号：
9321849
负责人：
Derek Alan Wainwright
金额：
$ 33.64万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321849
关键词：
Address Adult Affect Amino Acid Sequence Animals Apoptosis Area Binding Sites Brain Neoplasms Catabolism Cell Nucleus Cell Proliferation Cells ChIP-seq Clinical Complementary DNA Cytoplasm Cytotoxic T-Lymphocytes DNA Binding Data Diagnosis Dioxygenases Effectiveness Engraftment Enzymes Fractionation Gene Expression Genes Genetic Suppression Glioblastoma Glioma High Pressure Liquid Chromatography Human Immune Evasion Immune response Immunity Immunocompetent Immunodeficient Mouse Immunosuppression Immunosuppressive Agents Immunotherapy Impairment In Situ In Vitro Injectable Intracranial Neoplasms Investigation Kynurenine Laboratory Study Malignant neoplasm of brain Mass Spectrum Analysis Mediating Modeling Molecular Mus Mutate Mutation Nuclear Nuclear Extract Nuclear Localization Signal Patients Pharmacology Property Proteins Recurrence Regulatory T-Lymphocyte Resected Role Site-Directed Mutagenesis T cell response T-Lymphocyte Testing Therapeutic Tryptophan Tumor Immunity Work base cell motility cell type clinically relevant design glioma cell line in vivo indoleamine inhibitor/antagonist mouse model neoplastic cell novel overexpression reconstitution response small hairpin RNA tumor tumor microenvironment

项目摘要

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.

摘要