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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：
10721993
负责人：
Kayvan R Keshari
金额：
$ 32.45万
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/10721993
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 antagonist 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 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.

摘要