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.

抽象的胶质母细胞瘤多形（GBM）是成年人中最常见和侵略性的脑肿瘤形式。中位数诊断后GBM患者的存活率为14.6个月。 GBM的一致特征是肿瘤内存在损害患者抗GBM免疫反应的免疫抑制调节T细胞（TREG），与吲哚胺2,3二氧酶1（IDO1）的表达相吻合，这是一种限制酶，可转换色氨酸（TRP）至kynurenine（Kyn）。利用原位合理和免疫能力的GL261-C57BL6 植入模型，我先前证明了shRNA介导的鼠类IDO1表达的抑制 GBM细胞显着降低了肿瘤内Treg的积累与细胞溶解T细胞反应一致导致完全肿瘤回归。该观察结果促使对药理抑制作用进行了调查 IDO1作为治疗诱导抗GBM免疫的一种手段。但是，令人惊讶的是，管理 IDO1抑制剂对肿瘤内Treg积累没有影响，也不对动物受试者存活。一个假设提供了这种悖论的解释，解决了遗传抑制 - 但不能 IDO1的肿瘤内Treg积累和针对GBM的效应T细胞反应，构成了这个建议。最近，我的实验室发现，肿瘤微环境中但没有GBM细胞的细胞是在GL261-C57BL6模型中，几乎所有IDO1介导的TRP均与Kyn分解代谢。这个观察结果，然而，提出了一个关于肿瘤细胞相关IDO1的作用的问题，其遗传抑制促进针对肿瘤的生产性T细胞反应。这个问题的潜在答案已经出现与我们发现IDO1定位于GBM细胞中的细胞核的发现相关。根据这些观察，我们提议：1）在人类GBM原位建立IDO1细胞类型表达和分解代谢，2）研究IDO1 在人GBM细胞中的表达和功能，至3）确定核IDO1在GBM细胞中的功能。这拟议的研究旨在调查旨在逆转的临床问题和方法神经胶质瘤的免疫抑制，这是患者有效免疫疗法合理设计的第一步患有无法治愈的脑癌。