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.

抽象的尽管最近的免疫疗法进展（检查点阻滞和适应性T细胞转移），但大多数患者实体瘤仍然没有反应或随后产生了对治疗的耐药性。我们的小组和其他人描述了一种免疫抗性机制，由代谢失调介导色氨酸（TRP）分解代谢，通过Kynurenine（Kyn） - 芳基烃受体（AHR）途径。这通过AHR产生Kyn和信号传导抑制CD8+和CD4+效应T细胞并增强免疫抑制细胞类型的产生，包括Foxp3+ CD4+ T细胞（Treg），髓样衍生的抑制细胞（MDSC）和M2极化肿瘤相关巨噬细胞（TAMS） - 发挥作用的细胞在限制抗肿瘤免疫力中的关键作用。我们建议通过IDO/TDO-KYN-图像信号传导活动 AHR途径，以优化组合药物治疗的时机（计划）该途径以及基于免疫的疗法）。在此提案中，我们计划：使用成像通过TRP – KYN-AHR途径更好地理解信号肿瘤微环境，通过使用双报告基因系统监测AHR转录活性。我们有成功地开发了DRE（二恶英响应增强剂）-AHR报告基因系统，以：1）量化 AHR参与的动力学在体外刺激与不同的激动剂/拮抗剂及其ITS的动力学与TME不同成分的表型变化的相关性：癌细胞，巨噬细胞和T细胞； 2）;在肿瘤期间使用生物传感器系统监测体内AHR途径激活的动态 IDO/表达TDO的癌症模型的进展3）评估AHR激活的体内动力学对理论干预措施（PD-1/CTLA-4桶，T细胞疗法）的反应4）设计基于记者测定法随着时间的流逝，AHR活动； 4）评估临床翻译的潜力。这种方法解决了未满足的需求，并且由4位专家在领域和我们最近在自然传播中的出版物 - 请参阅支持信。