Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses.
Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses.
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DOI：
10.7554/elife.04177
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发表时间：
2014-08-22
期刊：
影响因子：
7.7
通讯作者：
Taniguchi T
中科院分区：
文献类型：
--
作者：
Chiba S;Ikushima H;Ueki H;Yanai H;Kimura Y;Hangai S;Nishio J;Negishi H;Tamura T;Saijo S;Iwakura Y;Taniguchi T
肿瘤细胞的根除需要与免疫系统细胞进行通讯并由其发出信号。自然杀伤（NK）细胞是天然免疫系统中至关重要的肿瘤杀伤效应细胞；然而，对于其他免疫细胞是否以及如何识别肿瘤细胞以协助NK细胞，人们知之甚少。在此，我们表明树突状细胞和巨噬细胞上表达的天然免疫受体Dectin - 1对于NK细胞介导的对高水平表达N - 聚糖结构的肿瘤细胞的杀伤至关重要。这些肿瘤细胞对受体的识别会激活IRF5转录因子以及下游基因的诱导，从而使NK细胞具有完全的杀肿瘤活性。与此一致的是，我们发现Dectin - 1或IRF5基因缺陷的小鼠体内肿瘤生长加剧。Dectin - 1在肿瘤细胞识别和信号传导中的关键作用可能为抗肿瘤免疫系统提供新的见解，并具有治疗意义。
DOI: http://dx.doi.org/10.7554/eLife.04177.001
当体内细胞不受控制地生长和分裂时，就会形成癌性肿瘤。一个人从癌症中康复的可能性差异很大，并且通常取决于癌症的类型以及治疗开始时疾病的严重程度。因此，研究人员对发现身体如何对癌细胞作出反应很感兴趣。
抵御感染和疾病的第一道防线是身体的天然免疫系统，它包括一组被称为白细胞的免疫细胞。这些细胞在身体的器官和组织中巡逻，以便对病原体以及受损、应激或其他异常的宿主细胞立即作出反应。在白细胞中，自然杀伤细胞参与识别和摧毁肿瘤细胞。然而，其他免疫细胞是否以及如何帮助自然杀伤细胞摧毁肿瘤尚不清楚。此外，尽管免疫细胞通过产生被称为模式识别受体的蛋白质来检测病原体和受损细胞，但这些受体是否也能检测肿瘤细胞尚不得而知。
在此，千叶等人揭示了另外两种免疫细胞——树突状细胞和巨噬细胞——在帮助自然杀伤细胞防止小鼠体内肿瘤生长方面起着至关重要的作用。树突状细胞和巨噬细胞产生一种名为Dectin - 1的模式识别受体，它能识别某些（但不是所有）类型肿瘤细胞表面上的一种分子。通过这种方式，Dectin - 1激活了一条关键的信号通路，并指导自然杀伤细胞的活动，使其能够有效地杀死肿瘤细胞。千叶等人发现，在缺乏Dectin - 1蛋白的小鼠中，这些肿瘤生长得更快。
千叶等人的研究结果可能也有助于解释某些抗体——识别和中和细菌和病毒等外来物的蛋白质——在癌症治疗中的有效性。此外，Dectin - 1通路为研究提供了一条新途径，可能会带来新的癌症治疗方法。
DOI: http://dx.doi.org/10.7554/eLife.04177.002
The eradication of tumor cells requires communication to and signaling by cells of the immune system. Natural killer (NK) cells are essential tumor-killing effector cells of the innate immune system; however, little is known about whether or how other immune cells recognize tumor cells to assist NK cells. Here, we show that the innate immune receptor Dectin-1 expressed on dendritic cells and macrophages is critical to NK-mediated killing of tumor cells that express N-glycan structures at high levels. Receptor recognition of these tumor cells causes the activation of the IRF5 transcription factor and downstream gene induction for the full-blown tumoricidal activity of NK cells. Consistent with this, we show exacerbated in vivo tumor growth in mice genetically deficient in either Dectin-1 or IRF5. The critical contribution of Dectin-1 in the recognition of and signaling by tumor cells may offer new insight into the anti-tumor immune system with therapeutic implications. DOI: http://dx.doi.org/10.7554/eLife.04177.001 When cells in the body grow and divide uncontrollably, cancerous tumors can form. An individual's likelihood of recovering from cancer is highly variable and often depends on the type of cancer and the extent of the disease at the start of treatment. Researchers are therefore interested in discovering how the body responds against cancerous cells. The first line of defense against infection and disease is the body's innate immune system, which includes a suite of immune cells known as white blood cells. These cells patrol the body's organs and tissues in an effort to immediately respond to pathogens and damaged, stressed or otherwise abnormal host cells. Among white blood cells, natural killer cells are involved in identifying and destroying tumor cells. However, it was unclear whether or how other immune cells might help natural killer cells to destroy tumors. In addition, although immune cells detect pathogens and injured cells by producing proteins called pattern recognition receptors, it was unknown whether these receptors also detect tumor cells. Here, Chiba et al. reveal that two other types of immune cell—dendritic cells and macrophages—play essential roles in helping natural killer cells to prevent tumors from growing in mice. The dendritic cells and macrophages produce a pattern recognition receptor called Dectin-1 that recognizes a molecule found on the surface of some—but not all—types of tumor cell. In doing so, Dectin-1 activates a critical signaling pathway and directs the activity of the natural killer cells so that they can effectively kill tumor cells. Chiba et al. found that these tumors grew faster in mice that lack the Dectin-1 protein. The findings of Chiba et al. may also help to explain the effectiveness of certain antibodies—proteins that recognize and neutralize foreign objects such as bacteria and viruses—in cancer therapy. In addition, the Dectin-1 pathway presents a new avenue of research that may offer new cancer treatments. DOI: http://dx.doi.org/10.7554/eLife.04177.002