Tumor-derived exosomes antagonize innate antiviral immunity.
Liang GaoLin WangTong DaiKe JinZhengkui ZhangShuai WangFeng XiePengfei FangBing YangHuizhe HuangHans van DamFangfang ZhouJisheng LiuPublished in: Nature immunology (2018)
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.
Keyphrases
- epidermal growth factor receptor
- immune response
- tyrosine kinase
- transcription factor
- wild type
- small cell lung cancer
- dendritic cells
- advanced non small cell lung cancer
- stem cells
- mesenchymal stem cells
- endothelial cells
- high fat diet induced
- gene expression
- type diabetes
- adipose tissue
- young adults
- dna binding
- skeletal muscle
- extracorporeal membrane oxygenation