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Zhang Long Laboratory of Zhejiang University reveals the important role of tumor exosomes in regulating host innate immunity

 

Immunological defects can be caused by various conditions and diseases, including, for example, malignancy, organ or stem cell transplantation, systemic vasculitis, and connective tissue disease. Malignancies such as aggressive tumor cells can compromise innate immunity, but the mechanisms of this are completely unknown. The latest study from Zhang Long Lab of Zhejiang Univeristy reveals the important role of tumor-derived exosomes in regulating host innate immunity. This gives the first report on how the tumor cells could manage to shut off host innate immunity.

Their study 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. Mechanically, 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.

Graduate students Liang Gao, Lin Wang, Tong Dai, Zhengkui Zhang and Postdoc Ke Jin are the co-first authors of this study. Prof. Long Zhang and prof. Fangfang Zhou are the corresponding authors.This work was supported by a special program from Ministry of Science and Technology of China(2016YFA0502500), the Chinese National Natural Science Funds (31701232,31571460,31471315,31671457和91753139), PCSIRT, Jiangsu National Science Foundation (BK20150354 and Zhejiang outstanding youth fund (LR14C070001).

Link:https://www.nature.com/articles/s41590-017-0043-5