IDO1 and Immunotolerance in Glioblastoma

IDO1 和胶质母细胞瘤的免疫耐受

• 批准号: 10432043
• 负责人: Gary E Schiltz
• 金额: $ 62.83万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432043
• 关键词: Address; Adult; Affect; Amino Acids; Autologous; Binding; Biodistribution; Brain Glioblastoma; Brain Neoplasms; Cells; Characteristics; Clinical; Complement Factor H; Complex; Data; Development; Dioxygenases; Enhancers; Enzyme Inhibitor Drugs; Enzymes; Essential Amino Acids; FOXP3 gene; Future; Generations; Glioblastoma; Human; IL2RA gene; Immune; Immune response; Immunobiology; Immunosuppression; Immunotherapy; Intracranial Neoplasms; Investigation; Knowledge; Kynurenine; Lead; Malignant neoplasm of brain; Manuscripts; Mediating; Metabolic; Microarray Analysis; Molecular; Mus; National Institute of Neurological Disorders and Stroke; National Research Service Awards; Nature; Newly Diagnosed; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phase III Clinical Trials; Productivity; Property; Protac; Proteins; Publications; Recurrence; Regulation; Regulatory T-Lymphocyte; Research; Resected; Small Interfering RNA; Structure-Activity Relationship; T-Lymphocyte; Testing; Therapeutic; Treatment outcome; Tryptophan; Tryptophan Metabolism Pathway; Tumor Immunity; Tumor-infiltrating immune cells; United States National Institutes of Health; Up-Regulation; Work; Xenograft procedure; anti-tumor immune response; anticancer research; base; cancer type; design; experimental study; expression vector; follow-up; humanized mouse; immune checkpoint blockade; immune resistance; improved; in vivo; indoleamine; interest; mouse model; multicatalytic endopeptidase complex; neuro-oncology; novel; novel therapeutic intervention; novel therapeutics; protein degradation; reconstitution; recruit; resistance mechanism; success; tool; ubiquitin-protein ligase; vector

PROJECT SUMMARY This R01 renewal proposal intends to extend the PI's past productivity that includes 35 publications since the year, 2016, including 3 senior-authored manuscripts in Clinical Cancer Research and 2 additional bodies of work that are under review in Neuro-Oncology and Nature. The scientific premise of the PI's renewal application is an extension of continuous NIH/NINDS F32 (Postdoctoral NRSA), NIH/NINDS K99/R00 (Pathway To Independence) and NIH/NINDS R01 support that have collectively focused on the investigation of indoleamine 2,3 dioxygenase 1 (IDO; IDO1) in glioblastoma (GBM). IDO is expressed in >90% of all patient-resected GBM and potently suppresses the anti-GBM immune response. IDO expression is increased by GBM-infiltrating T cells and therefore represents a key mechanism of resistance to immune-based therapies, since targeted approaches that aim to enhance T cell infiltration into GBM, will in-turn, result in a compensatory increase of IDO expression and suppression of the anti-GBM immune response. Importantly, the high intratumoral IDO expression is associated with significantly decreased GBM patient survival and increased immunosuppressive regulatory T cells (CD4+CD25+FoxP3+). Since IDO is canonically characterized as a rate-limiting enzyme that metabolizes the essential amino acid, tryptophan (Trp), into the downstream metabolite, kynurenine (Kyn), the depletion of Trp and/or accumulation of Kyn has been the presumed mechanism of how IDO suppresses the anti-GBM immune response. However, our work has challenged this hypothesis, supported in-part through the creation of IDO-deficient murine GBM cells reconstituted with either (i) empty expression vector, (ii) a vector expressing wild-type IDO, (iii) or a vector expressing enzyme-inactive IDO. When intracranially-engrafted into the syngeneic mouse brain, GBM cell IDO expression increases Tregs and decreases survival independent of tryptophan metabolism. Our collective results indicate that GBM cell IDO represents a complex mechanism of immune resistance that has motivated our development of IDO-proteolysis targeting chimeras (IDO-PROTACs) - compounds that bind to IDO protein and recruit an E3 ubiquitin ligase to facilitate proteasome degradation. IDO-PROTACs enable experiments to address IDO immunosuppressive effects that are enzyme independent. The aims of our proposal are therefore to (i) investigate the mechanism responsible for GBM cell IDO enzyme independent immunosuppression and (ii) design, create and optimize novel IDO-PROTACs that mediate IDO protein degradation in human GBM cells. Determination of how IDO suppresses the immune response combined with the generation of potent IDO-PROTACs will address knowledge gaps about GBM immunobiology while also improving treatment outcomes of GBM patients that are co-treated with immunotherapy and IDO-PROTACs.

项目摘要 该R01续签提案打算延长PI的过去生产率，其中包括35个出版物，因为 2016年，包括3个临床癌症研究中的高级手稿和另外2个工作机构 在神经肿瘤学和自然中正在综述。 PI更新应用的科学前提是 连续NIH/NINDS F32（博士后NRSA）的扩展，NIH/NINDS K99/R00（通往通往的途径 独立）和NIH/NINDS R01支持集体研究吲哚美碱 胶质母细胞瘤（GBM）中的2,3二氧酶1（IDO; IDO1）。 IDO以> 90％的所有患者指定的GBM表示 并有效抑制抗GBM免疫反应。 IDO表达通过GBM浸润t增加 细胞，因此代表了对免疫疗法抗性的关键机制，因为 旨在增强T细胞浸润到GBM的方法，将导致IDO的补偿性增加 抗GBM免疫反应的表达和抑制。重要的是，高肿瘤内IDO 表达与GBM患者生存率显着降低和免疫抑制有关 调节性T细胞（CD4+CD25+FOXP3+）。由于IDO在规范上被认为是限速酶 将必需氨基酸的色氨酸（TRP）代谢到下游代谢物，kynurenine（Kyn）， TRP的耗竭和/或Kyn的积累是IDO如何抑制的推测机制 抗GBM免疫反应。但是，我们的工作对这一假设提出了质疑，并通过 用（i）空表达矢量重构的IDO缺陷鼠GBM细胞，（ii）矢量 表达野生型IDO，（iii）或表达酶不活跃的IDO的矢量。当颅内移植成 同性小鼠大脑，GBM细胞IDO表达增加了Tregs，并降低了与生存的降低无关 色氨酸代谢。我们的集体结果表明，GBM Cell IDO代表了一个复杂的机制 免疫抵抗力激发了我们针对嵌合体的IDO蛋白质分解的发展（IDO-PROTACS） - 与IDO蛋白结合并募集E3泛素连接酶以促进蛋白酶体降解的化合物。 IDO-PROTACS使实验能够解决独立于酶的IDO免疫抑制作用。 因此，我们提案的目的是（i）研究负责GBM细胞IDO酶的机制 独立的免疫抑制和（ii）设计，创建和优化介导IDO的新型Ido-Protacs 人GBM细胞中的蛋白质降解。确定IDO如何抑制免疫反应的合并 随着产生有效的Ido-Protacs的产生，将解决有关GBM免疫生物学的知识差距 改善与免疫疗法和IDO-PROTAC共同治疗的GBM患者的治疗结果。