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

• 批准号: 10220621
• 负责人: Ronald George Blasberg
• 金额: $ 63.37万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 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/10220621
• 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; 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; 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; base; 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; macrophage; neoplastic cell; novel; overexpression; personalized approach; pre-clinical; prevent; programmed cell death protein 1; recruit; resistance mechanism; response; success; targeted agent; therapy design; therapy resistant; transcription factor; tumor; tumor microenvironment; tumor progression

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获得性耐药性。我们组和 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) - 芳烃受体 (AHR) 途径进行分解代谢。这 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 在限制抗肿瘤免疫中发挥关键作用。我们建议通过 IDO/TDO-Kyn- 来对信号活动进行成像 AHR途径，以优化联合药物治疗的时机（安排）（针对 该途径以及基于免疫的疗法）。 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 转录活性来调节肿瘤微环境。我们有 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 通路激活的动态 表达 IDO/TDO 的癌症模型中的进展 3) 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，拟议的策略得到了 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。