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

摘要 尽管最近在免疫治疗（检查点阻断和过继性T细胞转移）方面取得了进展，但大多数患者仍不能接受免疫治疗。 实体瘤仍然没有反应或随后对治疗产生获得性抗性。本集团与 其他人已经描述了一种免疫抗性机制， 色氨酸（Trp）催化剂通过犬尿氨酸（Kyn）-芳烃受体（AHR）途径。的 Kyn的产生和通过AHR的信号传导抑制了CD 8+和CD 4+效应T细胞，并增强了 免疫抑制细胞类型的产生，包括FoxP 3 + CD 4 + T细胞（T细胞）、骨髓来源的 抑制细胞（MDSC）和M2极化的肿瘤相关巨噬细胞（TAMs）-细胞，这些细胞发挥着 在限制抗肿瘤免疫中起关键作用。我们建议通过IDO/TDO-Kyn成像信号活动， AHR途径，以优化联合药物治疗的时机（安排）（治疗目标 该途径沿着基于免疫的疗法）。 在这项提案中，我们计划：使用成像来更好地了解通过Trp-Kyn-AHR通路的信号转导， 肿瘤微环境，通过监测AHR转录活性使用双报告系统。我们有 成功开发了DRE（二恶英响应增强子）-AHR报告系统，以便：1）定量 在体外用不同激动剂/拮抗剂刺激时AHR的接合动力学及其 与TME的不同组分（癌细胞、巨噬细胞和T细胞）中的表型变化的相关性; 2）使用生物传感器系统在肿瘤发生期间监测AHR通路在体内的激活动态。 3）评估IDO/TDO表达癌症模型中AHR活化的体内动力学， 在相同模型中对治疗干预（PD-1/CTLA-4阻断，T细胞疗法）的反应4）设计 基于Trp-Kyn-AHR轴报告基因测定的免疫疗法与Trp-Kyn-AHR轴抑制相结合的疗法 AHR活性随时间的变化;以及4）评估临床转化的潜力。 这一办法解决了一个未得到满足的需求，拟议战略得到了联合国环境规划署4名专家的大力支持。 领域和我们最近在《自然通讯》上发表的文章-见支持信。

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.