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

基本信息

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
项目类别：
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

项目摘要

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.

每年有60,000名美国人的预后患有头颈部鳞状细胞癌（HNSCC）严峻，只有50％-60％的5年患者。手术，放射和化疗是使人衰弱。免疫疗法表现出希望，但仅受益于少数HNSCC患者。那仍然有未满足的医疗需要更好地了解该疾病并产生更有效的靶向疗法。我们的探索性研究将解决这两个目标。积累的证据表明AHR高度很高在不存在异种生物的情况下，包括HNSCC在内的许多癌症中表达并长期活跃（和无论肿瘤病因如何），由于它们的内源性AHR配体（包括色氨酸）的产生 Kynurenine（Kyn）途径中的代谢产物。这些配体的形成取决于IDO或TDO 其本身是AHR调节的，创建了AHR扩增循环。在负反馈循环中，ahr- 受调节的CYP1A1和CYP1B1降解内源配体和AHR调节的AHR复制器（AHRR）抑制AHR活动。我们假设“ AHR电路”的这些元素有助于稳态促进肿瘤侵袭性的AHR活性（例如，癌症干细胞诱导）。此外，我们假设这些oncometabolites通过极化AHR+巨噬细胞向免疫抑制作用免疫抑制肿瘤相关的巨噬细胞（TAM），诱导粒细胞髓样衍生抑制细胞（MDSC-GS）和/或偏向AHR+ T细胞向调节性T细胞（Tregs）。因此，我们的中心假设是AHR驱动产生色氨酸代谢物的自我维持的AHR电路增强肿瘤侵袭性并抑制肿瘤免疫力。该假设将在两个中进行检验具体目的：目标1：确定控制稳态AHR因素的相对贡献人和鼠类HNSCC线的信号传导和Kyn产生。 AHR，IDO，TDO，CYP1A1，CYP1B1， AHRR将被系统地删除，并假定AHR稳态的重置生物后果，评估。环境配体重置稳态的潜力也将可以确定。这些扰动的AHR电路后果将用于推进新的数学最终可以用来描述和预测AHR活性及其生物学后果的模型。 AIM 2：确定AHR在HNSCC中充当免疫定位调节剂的层次。这假设由AHR电路（AIM 1）产生AHR配体的恶性细胞（S）产生免疫抑制TAM，MDSC-GS和/或Treg将使用独特的鼠模型进行测试 HNSCC和AHRLYSM有条件的敲除小鼠。在翻译的Subaim中，我们将指出免疫学我们的第二代人商业许可的AHR抑制剂的目标（TAM，MDSC-GS和/或Tregs）。这些跨学科的合作研究将阐明AHR配体生产的动态，AHR的对HNSCC的贡献，而AHR作为HNSCC治疗的新免疫定位靶标。