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T细胞转移)方面取得了进展，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。我们的团队和 另一些人则描述了一种免疫抵抗机制，这种机制是通过代谢失调介导的。 色氨酸(Trp)通过犬尿氨酸(Kyn)-芳香烃受体(AHR)途径分解代谢。这个 Kyn的产生和通过AHR的信号通路抑制CD8和CD4效应T细胞并增强 免疫抑制细胞类型的产生，包括FoxP3CD4T细胞(Tregs)，髓系来源 抑制细胞(MDSCs)和M2极化的肿瘤相关巨噬细胞(TAMs)-发挥作用的细胞 在限制抗肿瘤免疫中的关键作用。我们建议通过ido/tdo-Kyn来映射信号活动- AHR途径，以优化联合药物治疗(靶向治疗)的时间(调度) 这条途径以及基于免疫的疗法)。 在这项提案中，我们计划：使用成像来更好地理解通过Trp-Kyn-AHR途径的信号 肿瘤微环境，通过使用双重报告系统监测AHR转录活性。我们有 成功开发了DRE(二恶英响应增强剂)-AHR报告系统，以：1)定量 不同激动剂/拮抗剂体外刺激下AHR的结合动力学及其意义 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)利用生物传感器系统在体内监测肿瘤过程中AHR通路的激活动态 表达IDO/TDO的肿瘤模型的研究进展3)评价AHR在体内的激活动力学 对相同模型中的治疗干预(PD-1/CTLA-4阻断、T细胞治疗)的反应4)设计 抑制Trp-Kyn-AHR轴与免疫治疗相结合的治疗基于报告分析 AHR活性随时间的变化；以及4)评估临床翻译的潜力。 这种方法解决了未得到满足的需求，拟议的战略得到了以下领域4名专家的大力支持 菲尔德和我们最近在《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.