Endogenous and Environmental AHR Ligands in Head and Neck Cancer Aggression and Immunosuppression

头颈癌侵袭和免疫抑制中的内源性和环境 AHR 配体

• 批准号: 9752872
• 负责人: David H Sherr
• 金额: $ 24.75万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752872
• 关键词: Acute; Address; Adverse effects; Aggressive behavior; American; Aryl Hydrocarbon Receptor; Automobile Driving; Biological; Biology; Boston; CYP1A1 gene; CYP1B1 gene; Cell Line; Cells; Chemicals; Chronic; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Custom; Dana-Farber Cancer Institute; Development; Diagnosis; Disease; Elements; Enzymes; Etiology; Feedback; Generations; Genes; Goals; Grant; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Immune Targeting; Immune checkpoint inhibitor; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In complete remission; Interdisciplinary Study; Knockout Mice; Kynurenine; Ligands; Light; Malignant Neoplasms; Mathematics; Medical; Minority; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid-derived suppressor cells; Neoplasm Metastasis; Oncologist; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Positioning Attribute; Production; Property; Proteins; Radiation; Receptor Signaling; Regulatory Element; Regulatory T-Lymphocyte; T-Cell Receptor; Testing; Tryptophan; Tumor Immunity; Tumor-associated macrophages; Universities; Variant; Work; Xenobiotics; adverse outcome; aryl hydrocarbon receptor ligand; cancer cell; cancer immunotherapy; cancer initiation; cancer stem cell; chemotherapy; design; environmental chemical; granulocyte; immune checkpoint; indole-2,3-dioxygenase; inhibitor/antagonist; innovation; interdisciplinary approach; macrophage; mathematical model; microbial; mouse model; mouth squamous cell carcinoma; nano-string; neoplastic cell; novel; outcome forecast; predictive modeling; receptor expression; recruit; stemness; targeted treatment; tool; tumor

The prognosis for the 60,000 Americans diagnosed each year with head and neck squamous cell carcinoma (HNSCC) is grim with only 50%-60% of patients surviving 5 years. Surgery, radiation and chemotherapy are debilitating. Immunotherapy shows promise but benefits only a minority of HNSCC patients. Thus, there is still an unmet medical need to better understand the disease and to generate more effective targeted therapeutics. Our exploratory study will address these two goals. Accumulating evidence indicates that the AHR is highly expressed and chronically active in many cancers, including HNSCC, in the absence of xenobiotics (and regardless of tumor etiology), by virtue of their production of endogenous AHR ligands including tryptophan- derived metabolites in the Kynurenine (Kyn) pathway. Formation of these ligands is dependent on IDO or TDO which themselves are AHR regulated, creating an AHR amplification loop. In negative feedback loops, AHR- regulated CYP1A1 and CYP1B1 degrade endogenous ligands and AHR-regulated AHR repressor (AHRR) suppresses AHR activity. We postulate that these elements of an “AHR circuit” contribute to a steady-state of AHR activity which drives tumor aggression (e.g., cancer stem cell induction). Furthermore, we postulate that these oncometabolites contribute to immunosuppression by polarizing AHR+ macrophages towards immunosuppressive tumor-associated macrophages (TAMs), inducing granulocytic myeloid-derived suppressor cells (MDSC-Gs), and/or skewing AHR+ T cells towards regulatory T cells (Tregs). Therefore, our central hypothesis is that the AHR drives a self-sustaining AHR circuit that generates tryptophan metabolites which enhance tumor aggressiveness and suppress tumor immunity. This hypothesis will be tested in two specific aims: Aim 1: Determine the relative contribution of factors controlling steady-state AHR signaling and Kyn production in human and murine HNSCC lines. AHR, IDO, TDO, CYP1A1, CYP1B1, and AHRR will be systematically deleted and a postulated resetting of the AHR steady-state, along with its biological consequences, assessed. The potential for environmental ligands to reset the steady-state also will be determined. AHR circuit consequences of these perturbations will be used to advance a novel mathematical model that, ultimately, can be used to describe and predict AHR activity and its biological consequences. Aim 2: Determine at what level the AHR acts as an immune checkpoint regulator in HNSCC. The hypothesis that malignant cells producing AHR ligand(s), by virtue of the AHR circuit (Aim 1), generate immunosuppressive TAMs, MDSC-Gs, and/or Tregs will be tested using unique orthotopic models of murine HNSCC and AHRLysM conditional knockout mice. In a translational subaim, we will pinpoint the immunologic target (TAMs, MDSC-Gs, and/or Tregs) of our second generation, commercially licensed AHR inhibitor. These interdisciplinary, collaborative studies will shed light on the dynamics of AHR ligand production, the AHR’s contribution to HNSCC, and the AHR as a new immune checkpoint target for HNSCC treatment.

每年被诊断患有头颈鳞状细胞癌的 60,000 名美国人的预后 (HNSCC) 情况严峻，只有 50%-60% 的患者能存活 5 年。手术、放疗和化疗是 使人衰弱。免疫疗法显示出前景，但仅对少数 HNSCC 患者有益。因此，仍然有 未满足的医疗需求，以更好地了解该疾病并产生更有效的靶向治疗方法。 我们的探索性研究将解决这两个目标。越来越多的证据表明 AHR 高度 在缺乏异生素（和 无论肿瘤病因如何），凭借其产生内源性 AHR 配体（包括色氨酸） 犬尿氨酸 (Kyn) 途径中的衍生代谢物。这些配体的形成取决于 IDO 或 TDO 它们本身受 AHR 调节，形成 AHR 放大回路。在负反馈循环中，AHR- 受调节的 CYP1A1 和 CYP1B1 降解内源性配体和 AHR 调节的 AHR 阻遏蛋白 (AHRR) 抑制 AHR 活性。我们假设“AHR 电路”的这些元素有助于稳定状态 驱动肿瘤侵袭的 AHR 活性（例如，癌症干细胞诱导）。此外，我们假设 这些肿瘤代谢物通过将 AHR+ 巨噬细胞极化至 免疫抑制肿瘤相关巨噬细胞（TAM），诱导粒细胞骨髓源性 抑制细胞 (MDSC-G)，和/或将 AHR+ T 细胞偏向调节性 T 细胞 (Treg)。因此，我们的 中心假设是 AHR 驱动一个自我维持的 AHR 回路，产生色氨酸代谢物 增强肿瘤侵袭性并抑制肿瘤免疫。该假设将分两部分进行检验 具体目标： 目标 1：确定控制稳态 AHR 的因素的相对贡献 人和鼠 HNSCC 系中的信号传导和 Kyn 产生。 AHR、IDO、TDO、CYP1A1、CYP1B1、 AHRR 将被系统地删除，并假设重置 AHR 稳态及其 生物学后果，已评估。环境配体重置稳态的潜力也将 被确定。这些扰动的 AHR 电路后果将用于推进一种新颖的数学方法 最终，该模型可用于描述和预测 AHR 活动及其生物学后果。 目标 2：确定 AHR 在 HNSCC 中发挥免疫检查点调节作用的水平。这 假设产生 AHR 配体的恶性细胞通过 AHR 回路（目标 1）产生 免疫抑制 TAM、MDSC-G 和/或 Tregs 将使用独特的小鼠原位模型进行测试 HNSCC 和 AHRLysM 条件敲除小鼠。在翻译子目标中，我们将查明免疫学 我们第二代商业许可的 AHR 抑制剂的靶点（TAM、MDSC-G 和/或 Tregs）。这些 跨学科的合作研究将揭示 AHR 配体生产的动态，AHR 的 对 HNSCC 的贡献，以及 AHR 作为 HNSCC 治疗的新免疫检查点目标。