Breaking down tumor immune privilege through targeted hypoxia reduction

项目摘要/摘要 肿瘤缺氧预示着所有癌症的不良结局，并且是公认的对两者都具有抵抗力的来源。 化疗和放射治疗。我们已经证明，T细胞不能在导致癌症的缺氧区茁壮成长 针对胰腺癌和前列腺癌等免疫性感冒指征的检查点封锁失败。而我们的 之前的工作依赖于我们的偶然发现，低氧激活的前体药物TH-302可以有效地 减少肿瘤缺氧，目前还没有研究确定减少肿瘤缺氧的最有效方法 癌症。从机制上讲，肿瘤缺氧是由于氧气供应减少和 肿瘤氧耗量增加。虽然这些影响中的每一种都有助于促进缺氧和核化 免疫抑制状态，对它们在建立低氧状态中的相对重要性一无所知 它们对缺氧区肿瘤浸润性T细胞的影响也不同。此外，我们还缺乏一个 了解影响缺氧减少持久性的因素，以及限制肿瘤生长的任何干预措施 恢复缺氧状态的能力。在更深的层面上，缺氧触发的精确分子信号，即 对间质中的髓样细胞和肌成纤维细胞进行重新编程，以适应低氧状态并获得 免疫抑制功能也尚不清楚。因此我们假设肿瘤缺氧和 髓系和肌成纤维细胞间质的相关免疫抑制编程可以减少 通过局部组织重塑和限制肿瘤氧代谢。我们的首要目标是 低氧激活的前药、氧化剂对低氧和免疫渗入调节的动力学研究 磷酸化(OxPhos)抑制剂和抗血管生成剂。对于每一节课，我们将建立动力学 通过它们减少缺氧，这种减少在治疗后的持久性，以及重新治疗是否可以 消除复发的低氧。这是第一次此类系统研究，不仅将揭示 在免疫增强的背景下减少肿瘤缺氧，但也将提供对相对 氧供应中断与肿瘤耗氧量升高对建立缺氧的贡献。 其次，我们将研究OxPhos抑制剂对肿瘤和T细胞代谢以及低氧的影响 健身。我们将评估针对复合体I的不同亚单位的三种OxPhos代谢抑制剂是如何， 影响肿瘤与T细胞代谢、功能和低氧适应。这些研究将提供关键的 洞察是否可以通过抑制肿瘤缺氧的方式来抑制肿瘤的氧耗 健身和免疫特权，不损害抗肿瘤免疫功能能力。第三个目标是 该建议利用在肿瘤髓系中缺乏缺氧诱导因子1-α(HIF1α)或HIF2α的小鼠 间质或肌成纤维细胞映射负责功能和代谢编程的下游信号 这些细胞对低氧的反应。这些研究将为临床减少缺氧提供重要的见解 以提高我们对“感冒”癌症的免疫治疗能力。

PROJECT SUMMARY/ABSTRACT Tumor hypoxia predicts poor outcomes across all cancers and is a well-established source of resistance to both chemo- and radiotherapy. We have shown that T cells fail to thrive in hypoxic zones of cancer underlying the failure of checkpoint blockade for immune “cold” indications such as pancreatic and prostate cancer. While our prior work relied on our serendipitous discovery that the hypoxia-activated prodrug, TH-302, could efficiently reduce tumor hypoxia, there have been no studies to identify the most effective means to reduce hypoxia in cancer. Mechanistically, tumor hypoxia results from the combination of diminished oxygen supply coupled with enhanced tumor oxygen consumption. While each of these influences helps to foster hypoxia and nucleate an immune suppressive state, nothing is known of their relative importance in establishment of the hypoxic state itself, nor of their differential impact on tumor-infiltrating T cells within hypoxic regions. Further, we lack an understanding of the factors governing durability of hypoxia-reduction, and of any interventions to limit tumors’ capacity to restore the hypoxic state. At a deeper level, the precise molecular signals triggered by hypoxia, which reprogram myeloid and myofibroblast cells in the stroma to adapt metabolically to the hypoxic state and acquire immune suppressive function also remain unclear. We therefore hypothesize that tumor hypoxia and associated immune suppressive programming of the myeloid and myofibroblast stroma can be reduced through both local tissue remodeling and through limitation of tumor oxygen metabolism. Our first aim is to determine the kinetics of hypoxia and immune infiltrate modulation by hypoxia-activated prodrugs, oxidative phosphorylation (OxPhos) inhibitors, and anti-angiogenic agents. For each class, we will establish the kinetics by which they reduce hypoxia, how durable that reduction is post-therapy, and whether re-treatment can eliminate re-emergent hypoxia. This first of its kind systematic study will not only reveal optimal approaches for reducing tumor hypoxia in an immune-potentiating context but will also provide insights into the relative contribution of disrupted oxygen supply versus elevated tumor oxygen consumption toward establishing hypoxia. Second, we will investigate the impact of OxPhos inhibitors on both tumor and T cell metabolism and hypoxic fitness. We will assess how three inhibitors of OxPhos metabolism, which target distinct subunits of Complex I, impact tumor versus T cell metabolism, function, and hypoxic adaptation. These studies will provide critical insight into whether tumor oxygen consumption can be inhibited in a manner which compromises tumor hypoxic fitness and immune privilege without damaging the functional capacity of anti-tumor immunity. The third aim of this proposal utilizes mice lacking hypoxia-inducible factor 1-alpha (HIF1α) or HIF2α in either their tumor myeloid stroma or myofibroblasts to map the downstream signals responsible for functional and metabolic programming of these cells in response to hypoxia. These studies will provide critical insights allowing clinical hypoxia reduction to improve and with it our capacity for immunotherapy of “cold” cancers.