Tumor-derived exosomes antagonize innate antiviral immunity
Tumor-derived exosomes antagonize innate antiviral immunity
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肿瘤来源的外泌体拮抗先天抗病毒免疫。
DOI：
10.1038/s41590-017-0043-5
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发表时间：
2018-03-01
影响因子：
30.5
通讯作者：
Zhang, Long
中科院分区：
文献类型：
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作者：
Gao, Liang;Wang, Lin;Zhang, Long
恶性肿瘤可以损害先天免疫，但其机制在很大程度上是未知的。在这里，我们发现，通过肿瘤源性外泌体（TEXs），癌症能够将活化的表皮生长因子受体（EGFR）转移到宿主巨噬细胞，从而抑制先天抗病毒免疫。人类激酶组的筛选发现巨噬细胞中的激酶MEKK2是tex传递的EGFR的效应物，负调控抗病毒免疫反应。在实验性肿瘤植入的背景下，mekk2缺陷小鼠比野生型小鼠更能抵抗病毒感染。向小鼠注射TEXs以依赖EGFR和mekk2的方式降低先天免疫，增加病毒载量和增加发病率。MEKK2磷酸化IRF3， IRF3是产生I型干扰素的关键转录因子；这触发了IRF3的多泛素化，并阻断了病毒感染后IRF3的二聚化、向细胞核的易位和转录活性。这些发现确定了癌细胞可以抑制宿主先天免疫并可能导致癌症患者免疫功能低下的机制。
Malignancies can compromise innate immunity, but the mechanisms of this are largely unknown. Here we found that, via tumor-derived exosomes (TEXs), cancers were able to transfer activated epidermal growth factor receptor (EGFR) to host macrophages and thereby suppress innate antiviral immunity. Screening of the human kinome identified the kinase MEKK2 in macrophages as an effector of TEX-delivered EGFR that negatively regulated the antiviral immune response. In the context of experimental tumor implantation, MEKK2-deficient mice were more resistant to viral infection than were wild-type mice. Injection of TEXs into mice reduced innate immunity, increased viral load and increased morbidity in an EGFR- and MEKK2-dependent manner. MEKK2 phosphorylated IRF3, a transcription factor crucial for the production of type I interferons; this triggered poly-ubiquitination of IRF3 and blocked its dimerization, translocation to the nucleus and transcriptional activity after viral infection. These findings identify a mechanism by which cancer cells can dampen host innate immunity and potentially cause patients with cancer to become immunocompromised.