Image-guided Trp-IDO/TDO-Kyn-AHR pathway inhibition, combined with immunotherapy

图像引导 Trp-IDO/TDO-Kyn-AHR 通路抑制结合免疫治疗

基本信息

批准号：
10600027
负责人：
Kayvan R Keshari
金额：
$ 45.26万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10600027
关键词：
Address Adoptive Transfer Agonist Antigens Aryl Hydrocarbon Receptor Basic Science Biological Biological Assay Biological Markers Biological Models Biosensor CD4 Positive T Lymphocytes CD8B1 gene CTLA4 blockade Cancer Model Catabolism Cells Characteristics Clinical Combined Modality Therapy Communication Data Dioxins Drug Combinations Elements Enhancers Enzymes Evaluation FOXP3 gene Generations Genetic Transcription Glucose Glutamine Human Image Immune Immunooncology Immunosuppression Immunotherapy In Vitro Inflammatory Infrastructure Interdisciplinary Study Kinetics Kynurenine Letters Link Macrophage Malignant Neoplasms Mediating Metabolic Modeling Monitor Myelogenous Myeloid-derived suppressor cells Nature Nutritional Pathway interactions Patients Pharmacotherapy Phenotype Play Population Pre-Clinical Model Production Publications Receptor Activation Receptor Inhibition Records Regulatory T-Lymphocyte Reporter Research Resistance Role Schedule Signal Transduction Solid Neoplasm System T cell anergy T cell therapy T-Lymphocyte Therapeutic Intervention Time Tryptophan Tryptophan 2,3 Dioxygenase Tryptophanase Tumor Cell Line Tumor Immunity Tumor-associated macrophages antagonist cancer cell cancer type cell type clinical translation clinically relevant combinatorial design effector T cell experience image guided immune checkpoint blockade immune resistance improved in vivo neoplastic cell novel overexpression personalized approach pre-clinical prevent programmed cell death protein 1 rational design recruit resistance mechanism response success targeted agent therapy design therapy resistant transcription factor tumor tumor microenvironment tumor progression

项目摘要

ABSTRACT Despite recent progress in immunotherapy (checkpoint blockade and adoptive T cell transfer), most patients with solid tumors still do not respond or subsequently develop acquired resistance to therapy. Our group and others have described an immune resistance mechanism mediated by the metabolic dysregulation of Tryptophan (Trp) catabolism through the Kynurenine (Kyn) - aryl hydrocarbon receptor (AHR) pathway. The production of Kyn and signaling through the AHR suppresses CD8+ and CD4+ effector T cells and enhances the generation of immunosuppressive cell types, including FoxP3+CD4+ T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and M2-polarised tumor-associated macrophages (TAMs) - cells which play a critical role in limiting anti-tumor immunity. We propose to image signaling activity through the IDO/TDO-Kyn- AHR pathway, in order to optimize the timing (scheduling) of combination drug treatment (treatments targeting this pathway along with immune based therapies). In this proposal, we plan to: use imaging to better understand signaling through the Trp–Kyn-AHR pathway in the tumor microenvironment, by monitoring AHR transcriptional activity using dual reporter systems. We have successfully developed a DRE (dioxin responsive enhancers)-AHR reporter system in order to: 1) quantify the kinetics of engagement of the AHR upon in vitro stimulation with different agonists/antagonists and its correlation with phenotypic changes in different components of the TME: cancer cells, macrophage and T cells; 2); to monitor the dynamic of activation of the AHR pathway in vivo using a biosensor system during tumor progression in IDO/TDO-expressing cancer models 3) to evaluate the in vivo dynamics of AHR activation after response to therapeutic interventions (PD-1/CTLA-4 blockade, T cell therapy) in the same models 4) design therapies combining the inhibition of the Trp-Kyn-AHR axis with immune therapy based on reporter assays of the AHR activity over time; and 4) evaluate the potential for clinical translation. This approach addresses an unmet need and the proposed strategy is strongly supported by 4 experts in the field and our recent publication in Nature Communication– see letters of support.

抽象的尽管免疫疗法（检查点封锁和过继性 T 细胞转移）最近取得了进展，但大多数患者实体瘤仍然没有反应或随后对治疗产生耐药性。其他人描述了由代谢失调介导的免疫抵抗机制色氨酸 (Trp) 通过犬尿氨酸 (Kyn) - 芳基烃受体 (AHR) 途径进行分解代谢。 Kyn 的产生和通过 AHR 的信号传导抑制 CD8+ 和 CD4+ 效应 T 细胞并增强免疫抑制细胞类型的产生，包括骨髓来源的 FoxP3+CD4+ T 细胞 (Treg) 抑制细胞 (MDSC) 和 M2 极化肿瘤相关巨噬细胞 (TAM) - 发挥作用的细胞我们建议通过 IDO/TDO-Kyn- 来成像信号活动。 AHR途径，以优化联合药物治疗的时机（安排）（针对这沿着基于免疫疗法的途径）。在本提案中，我们计划：使用成像技术更好地理解 Trp-Kyn-AHR 通路中的信号传导通过使用双报告系统监测 AHR 转录活性，我们可以了解肿瘤微环境。成功开发了 DRE（二恶英响应增强剂）-AHR 报告系统，以便：1）量化不同激动剂/拮抗剂体外刺激时 AHR 的接合动力学及其与 TME 不同成分（癌细胞、巨噬细胞和 T 细胞）表型变化的相关性； 2);使用生物传感器系统监测肿瘤期间体内AHR通路的激活动态 3) 表达 IDO/TDO 的癌症模型中的进展，以评估 AHR 激活后的体内动态相同模型中对治疗干预（PD-1/CTLA-4 阻断、T 细胞治疗）的反应 4) 设计将 Trp-Kyn-AHR 轴抑制与基于报告基因检测的免疫疗法相结合的疗法随着时间的推移，AHR 活动；4) 评估临床转化的潜力。这种方法解决了未满足的需求，所提出的策略得到了 4 位专家的大力支持领域和我们最近在《自然通讯》上发表的文章——请参阅支持信。