Metabolic regulation of T cell fate and tumor immunity

描述（由申请人提供）：免疫治疗，其重点是增强宿主对肿瘤相关抗原的免疫力，代表了治疗癌症的重要手段，正在取得临床成功。成功操纵T细胞反应需要了解特定T细胞亚群如何影响癌症的发展和生长。例如，Th 1和Th 17细胞可以增强肿瘤发生。Treg细胞可以阻断抗肿瘤免疫应答，因此代表了成功的肿瘤免疫治疗的主要障碍之一。虽然Th 17细胞被认为是肿瘤支持细胞，但Th 17细胞与肿瘤免疫之间的关系一直存在争议。 T细胞命运决定中一个主要的未被重视的因素是代谢环境。作为研究T细胞分化决定的代谢调节的努力的一部分，我们发现缺氧诱导因子1（HIF-1）在驱动Th 17应答中起着关键作用。进一步的初步结果表明，缺乏这种分子导致肿瘤发生和进展减少。在本研究中，我们的目标是：（1）进一步剖析HIF-1在Th 17发育中的作用。我们将讨论HIF-1对Th 17谱系的贡献的广度和特定方面。我们还将探讨HIF-1作为人类治疗靶点的适用性;（2）我们将探索HIF-1在炎症诱导的癌症发生和癌症进展中调节Th 17和Treg反应的作用;（3）我们随后将使用这些体内癌症模型来测试HIF-1靶向的治疗潜力。在这些研究中，小鼠将用HIF-1抑制剂地高辛和吖啶黄治疗，我们将评估这些化合物单独或与Treg耗竭一起阻碍肿瘤生长的能力。根据我们的初步数据和过去的结果，这种策略有望具有有效的抗肿瘤作用，因为它应该同时破坏两种主要的促肿瘤免疫细胞群

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