Metabolic regulation of T cell fate and tumor immunity

描述(申请人提供)：免疫疗法的重点是增强宿主对肿瘤相关抗原的免疫力，是治疗癌症的重要手段，正在取得临床成功。T细胞反应的成功操作需要了解特定的T细胞亚群如何影响癌症的发展和生长。例如，Th1和Th17细胞可以增强肿瘤的发生。Treg细胞可以阻断抗肿瘤免疫反应，因此是肿瘤免疫治疗成功的主要障碍之一。虽然Tregs被认为是肿瘤支持细胞，但Th17细胞与肿瘤免疫之间的关系一直存在争议。 决定T细胞命运的一个主要因素是代谢环境。作为研究T细胞分化决定的代谢调控的一部分，我们发现低氧诱导因子1(HIF-1)在驱动Th17反应中发挥关键作用。进一步的初步结果表明，缺乏这种分子会导致肿瘤的启动和进展减少。在本提案中，我们的目标是：(1)进一步剖析HIF-1在Th17发育中的作用。我们将讨论HIF-1的广度和特定方面，S对Th17血统的贡献。我们还将探讨HIF-1作为治疗靶点在人类中的适用性；(2)我们将探讨HIF-1在调节Th17和Treg反应中在炎症诱导的癌症发生和癌症进展中的作用；(3)我们随后将使用这些体内癌症模型来测试HIF-1靶向治疗的潜力。在这些研究中，小鼠将接受HIF-1抑制剂、地高辛和丫黄素的治疗，我们将评估这些化合物单独或与Treg耗尽一起抑制肿瘤生长的能力。考虑到我们的初步数据和过去的结果，这种策略预计会有强大的抗肿瘤效果，同时破坏两个主要的促进肿瘤的免疫细胞群

DESCRIPTION (provided by applicant): Immunotherapy, which focuses on augmenting host immunity against tumor-associated antigens, represents an important means to treat cancer that is yielding clinical success. Successful manipulation of T cell responses requires understanding how particular T cell subsets influence cancer development and growth. For example, Th1 and Th17 cells can augment tumorigenesis. Treg cells can block anti-tumor immune responses and thus represents one of the main obstacles to successful tumor immunotherapy. While Tregs are recognized as tumor supporting cells, the relationship between Th17 cells and tumor immunity has been controversial. A major unappreciated element in T cell fate decisions is the metabolic environment. As part of an effort to study the metabolic regulation of T cell differentiation decisions, we have discovered that hypoxia inducible factor 1 (HIF-1) plays a critical role in driving the Th17 response. Further preliminary results suggest that lack of this molecule results in reduced tumor initiation and progression. In this proposal, we aim to: (1) further dissect the role of HIF-1 in Th17 development. We will address the breadth, and particular facets of HIF-1's contribution to the Th17 lineage. We will also touch on the suitability of HIF-1 as a therapeutic target in humans; (2) we will explore the role of HIF-1 in regulating the Th17 and Treg responses in inflammation-induced carcinogenesis and cancer progression; (3) we will subsequently use these in vivo cancer models to test the therapeutic potential of HIF-1 targeting. In these studies mice will be treated with the HIF-1 inhibitors, Digoxin and Acriflavine and we will evaluate the ability of these compounds to impede tumor growth either alone or in concert with Treg depletion. Such a strategy is expected to have potent anti-tumor effects as it should, given our preliminary data and past results, simultaneously sabotage two major tumor- promoting immune cell populations