Life Sciences Institute and Innovation Center for Cell Signaling Network, Hangzhou, Zhejiang, China.
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
Nat Immunol. 2018 Mar;19(3):233-245. doi: 10.1038/s41590-017-0043-5. Epub 2018 Jan 22.
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.
恶性肿瘤可能会损害先天免疫，但这方面的机制在很大程度上尚不清楚。在这里，我们发现，肿瘤来源的外泌体（TEXs）能够将激活的表皮生长因子受体（EGFR）转移到宿主巨噬细胞中，从而抑制先天抗病毒免疫。对人类激酶组的筛选鉴定出巨噬细胞中的激酶 MEKK2 是 TEX 递送的 EGFR 的效应物，它负调控抗病毒免疫反应。在实验性肿瘤植入的情况下，与野生型小鼠相比，MEKK2 缺陷型小鼠对病毒感染的抵抗力更强。外泌体注射到小鼠体内会以 EGFR 和 MEKK2 依赖的方式降低先天免疫、增加病毒载量并增加发病率。MEKK2 磷酸化 IRF3，IRF3 是产生 I 型干扰素所必需的转录因子；这触发了 IRF3 的多聚泛素化，并阻止了其在病毒感染后的二聚化、易位到细胞核和转录活性。这些发现确定了一种机制，即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受损。
