Polymorphonuclear neutrophils (PMNs) are increasingly recognized to influence solid tumor development, but why their effects are so context dependent and even frequently divergent remains poorly understood. Using an autochthonous mouse model of uterine cancer and the administration of respiratory hyperoxia as a means to improve tumor oxygenation, we provide in vivo evidence that hypoxia is a potent determinant of tumor-associated PMN phenotypes and direct PMN–tumor cell interactions. Upon relief of tumor hypoxia, PMNs were recruited less intensely to the tumor-bearing uterus, but the recruited cells much more effectively killed tumor cells, an activity our data moreover suggested was mediated via their production of NADPH oxidase–derived reactive oxygen species and MMP-9. Simultaneously, their ability to promote tumor cell proliferation, which appeared to be mediated via their production of neutrophil elastase, was rendered less effective. Relieving tumor hypoxia thus greatly improved net PMN-dependent tumor control, leading to a massive reduction in tumor burden. Remarkably, this outcome was T cell independent. Together, these findings identify key hypoxia-regulated molecular mechanisms through which PMNs directly induce tumor cell death and proliferation in vivo and suggest that the contrasting properties of PMNs in different tumor settings may in part reflect the effects of hypoxia on direct PMN–tumor cell interactions.

中文翻译：

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缓解肿瘤缺氧释放出嗜中性粒细胞的杀肿瘤潜力

越来越多地认识到多形核中性粒细胞（PMN）影响实体瘤的发展，但是为什么它们的作用如此依存于上下文，甚至经常发散，人们对此仍然知之甚少。使用子宫癌的小鼠模型并给予呼吸道高氧作为改善肿瘤氧合的一种手段，我们提供了体内证据，低氧是与肿瘤相关的PMN表型和直接的PMN-肿瘤细胞相互作用的有效决定因素。减轻肿瘤缺氧后，PMNs较不强烈地募集到荷瘤子宫，但是募集的细胞更有效地杀死了肿瘤细胞，我们的数据还表明，这种活性是通过其产生NADPH氧化酶衍生的活性氧和MMP介导的。 -9。同时，它们促进肿瘤细胞增殖的能力 似乎是由于它们通过嗜中性粒细胞弹性蛋白酶的产生而介导的，因此效果较差。消除肿瘤缺氧从而大大改善了依赖于PMN的净肿瘤控制，从而大大降低了肿瘤负担。值得注意的是，该结果与T细胞无关。在一起，这些发现确定了缺氧调节的关键分子机制，PMN通过这些分子机制直接诱导体内肿瘤细胞的死亡和增殖，并表明不同肿瘤背景下PMN的对比特性可能部分反映了缺氧对直接PMN-肿瘤细胞相互作用的影响。 。该结果与T细胞无关。在一起，这些发现确定了缺氧调节的关键分子机制，PMN通过这些分子机制直接诱导体内肿瘤细胞的死亡和增殖，并表明不同肿瘤背景下PMN的对比特性可能部分反映了缺氧对直接PMN-肿瘤细胞相互作用的影响。 。该结果与T细胞无关。在一起，这些发现确定了缺氧调节的关键分子机制，PMN通过这些分子机制直接诱导体内肿瘤细胞的死亡和增殖，并表明不同肿瘤背景下PMN的对比特性可能部分反映了缺氧对直接PMN-肿瘤细胞相互作用的影响。 。