Enhanced tumor immune surveillance through neutrophil reprogramming due to Tollip deficiency.
Enhanced tumor immune surveillance through neutrophil reprogramming due to Tollip deficiency.
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DOI：
10.1172/jci.insight.122939
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发表时间：
2019-01
期刊：
影响因子：
8
通讯作者：
Yao Zhang;Christina Lee;S. Geng;Liwu Li
中科院分区：
文献类型：
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作者：
Yao Zhang;Christina Lee;S. Geng;Liwu Li
尽管肿瘤免疫环境对肿瘤发生和肿瘤消退调节的重要性越来越清楚，但大多数与肿瘤免疫治疗相关的研究都集中在适应性免疫细胞上，而先天白细胞（如中性粒细胞）的作用和调节仍然存在争议，而且定义较少。在这里，我们观察到选择性缺失Tollip（一种关键的先天免疫细胞调节剂）导致化学诱导的结直肠癌模型中肿瘤免疫监视增强。tollip缺陷中性粒细胞通过增强共刺激分子CD80的表达，降低抑制分子PD-L1的表达，显著提高T细胞的活化。从机制上讲，Tollip缺陷增加了STAT5，降低了STAT1，这两个转录因子分别负责CD80和PD-L1的表达。通过过继性转移，我们证明缺乏tollip的中性粒细胞，而不是缺乏tollip的单核细胞，足以增强肿瘤免疫监视并减少体内结直肠癌负担。我们的数据揭示了一种有利于增强抗肿瘤免疫环境的中性粒细胞功能重编程策略。
Although the importance of the tumor immune environment for the modulation of tumorigenesis and tumor regression is becoming increasingly clear, most of the research related to tumor-immune therapies has focused on adaptive immune cells, while the role and regulation of innate leukocytes such as neutrophils remains controversial and less defined. Here we observed that the selective deletion of Tollip, a key innate immune-cell modulator, led to enhanced tumor immune surveillance in a chemically induced colorectal cancer model. Tollip-deficient neutrophils significantly elevated T cell activation through enhanced expression of the costimulatory molecule CD80, and reduced expression of the inhibitory molecule PD-L1. Mechanistically, Tollip deficiency increased STAT5 and reduced STAT1, the transcription factors responsible for the expression of CD80 and PD-L1, respectively. Through adoptive transfer, we demonstrate that Tollip-deficient neutrophils, but not Tollip-deficient monocytes, are sufficient to drive enhanced tumor immune surveillance and reduced colorectal cancer burden in vivo. Our data reveal a strategy for the reprogramming of neutrophil functions conducive for the enhancement of the antitumor immune environment.