ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung
ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung
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DOI：
10.1038/s41590-020-0745-y
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发表时间：
2020-08-03
影响因子：
30.5
通讯作者：
Halim, Timotheus Y. F.
中科院分区：
文献类型：
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作者：
Schuijs, Martijn J.;Png, Shaun;Halim, Timotheus Y. F.
转移是癌症相关死亡的主要原因，肺是常见的受累器官。我们发现，肺驻留的2型固有淋巴细胞（ILC2s）的激活协调了对自然杀伤（NK）细胞介导的固有抗肿瘤免疫的抑制，导致肺转移增加和死亡率上升。利用多种肺转移模型，我们表明肺中白细胞介素（IL）-33依赖的ILC2激活在促进肿瘤负荷方面起核心作用。ILC2驱动的固有2型炎症伴随着肺NK细胞干扰素 -γ产生和细胞毒功能的显著局部抑制。ILC2对NK细胞的依赖性抑制是通过一种固有调节机制实现的，该机制依赖于IL - 5诱导的肺嗜酸性粒细胞增多，最终限制了NK细胞的代谢适应性。对IL - 33或IL - 5进行治疗性靶向可逆转NK细胞抑制并减轻癌症负荷。因此，我们揭示了IL - 33和ILC2s通过其抑制固有1型免疫的能力在促进肿瘤转移方面的重要作用。病理性2型固有淋巴细胞（ILC2s）主要与过敏有关。哈利姆及其同事证明，ILC2s通过募集抑制NK细胞功能的嗜酸性粒细胞来协调一种促转移途径。
Metastasis constitutes the primary cause of cancer-related deaths, with the lung being a commonly affected organ. We found that activation of lung-resident group 2 innate lymphoid cells (ILC2s) orchestrated suppression of natural killer (NK) cell-mediated innate antitumor immunity, leading to increased lung metastases and mortality. Using multiple models of lung metastasis, we show that interleukin (IL)-33-dependent ILC2 activation in the lung is involved centrally in promoting tumor burden. ILC2-driven innate type 2 inflammation is accompanied by profound local suppression of interferon-gamma production and cytotoxic function of lung NK cells. ILC2-dependent suppression of NK cells is elaborated via an innate regulatory mechanism, which is reliant on IL-5-induced lung eosinophilia, ultimately limiting the metabolic fitness of NK cells. Therapeutic targeting of IL-33 or IL-5 reversed NK cell suppression and alleviated cancer burden. Thus, we reveal an important function of IL-33 and ILC2s in promoting tumor metastasis via their capacity to suppress innate type 1 immunity.Pathological group 2 innate lymphoid cells (ILC2s) have mainly been implicated in allergy. Halim and colleagues demonstrate that ILC2s orchestrate a prometastatic pathway via the recruitment of eosinophils that suppress NK cell function.