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Nat Immunol. 2018 Mar;19(3):233-245. doi: 10.1038/s41590-017-0043-5. Epub 2018 Jan 22.

Tumor-derived exosomes antagonize innate antiviral immunity.

Author information

1
Life Sciences Institute and Innovation Center for Cell Signaling Network, Hangzhou, Zhejiang, China.
2
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
3
Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
4
Faculty of Basic Medical Sciences, Chonqing Medical University, Chongqing, China.
5
Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, The Netherlands.
6
Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China. zhoufangfang@suda.edu.cn.
7
Life Sciences Institute and Innovation Center for Cell Signaling Network, Hangzhou, Zhejiang, China. l_zhang@zju.edu.cn.

Abstract

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.

PMID:
29358709
DOI:
10.1038/s41590-017-0043-5

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