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

每年诊断为头颈部鳞状细胞癌的60，000名美国人的预后 （HNSCC）是严峻的，只有50%-60%的患者存活5年。手术、放疗和化疗 使人虚弱免疫疗法显示出希望，但仅使少数HNSCC患者受益。因此， 更好地了解疾病并产生更有效的靶向治疗的未满足的医疗需求。 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是高度 在不存在外源性物质的情况下，在许多癌症（包括HNSCC）中表达并长期活性（和 无论肿瘤病因学如何），由于它们产生内源性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 其本身是AHR调节的，从而产生AHR放大环。在负反馈回路中，AHR- 受调节的CYP 1A 1和CYP 1B 1降解内源性配体和AHR调节的AHR阻遏物（AHRR） 抑制AHR活性。我们假设，“AHR回路”的这些元件有助于维持一种稳态， 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， 这些肿瘤细胞通过将AHR+巨噬细胞极化至 免疫抑制性肿瘤相关巨噬细胞（TAM），诱导粒细胞髓源性 抑制细胞（MDSC-Gs），和/或使AHR+ T细胞偏向调节性T细胞（THR）。所以我们的 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 其增强肿瘤侵袭性并抑制肿瘤免疫。这一假设将在两个 具体目标：目标1：确定控制稳态AHR的因素的相对贡献 在人和鼠HNSCC系中的信号传导和Kyn产生。AHR、IDO、TDO、CYP1A1、CYP1B1、 和AHRR将被系统地删除，并假设重置AHR稳态，沿着， 生物学后果评估环境配体重置稳态的可能性也将 被确定。这些扰动的AHR电路后果将用于推进一种新的数学模型。 该模型最终可用于描述和预测AHR活性及其生物学后果。 目的2：确定AHR在HNSCC中作为免疫检查点调节剂的水平。的 假设产生AHR配体的恶性细胞，通过AHR回路（目的1）， 免疫抑制性TAM、MDSC-G和/或TGFAP将使用鼠的独特原位模型进行测试。 HNSCC和AHRLysM条件性敲除小鼠。在一个翻译的子目标，我们将查明免疫 我们的第二代商业许可的AHR抑制剂的靶点（TAM、MDSC-G和/或THRG）。这些 跨学科的合作研究将揭示AHR配体生产的动力学，AHR的 因此，本发明的目的在于提供一种用于HNSCC治疗的新的免疫检查点靶点，即AHR对HNSCC的贡献，以及AHR作为HNSCC治疗的新免疫检查点靶点。

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.