Journal Article

Tumor-derived exosomes antagonize innate antiviral immunity

Jin, Ke, Yang, Bing, Gao, Liang, Wang, Shuai, van Dam, Hans, Xie, Feng, Fang, Pengfei, Zhang, Long, Dai, Tong, Wang, Lin, Zhou, Fangfang, Zhang, Zhengkui, Huang, Huizhe

2018

Overview

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. Cancer can be associated with alterations in innate immunity. Gao et al. demonstrate that these alterations arise from immunomodulatory exosomes released by tumors, which then dampen the production of type I interferons by macrophages.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Adult / Animals / Antiviral drugs / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer cells / Dimerization / Disease susceptibility / Diseases / Epidermal growth factor / Epidermal growth factor receptors / Epidermal growth factors / ErbB Receptors - immunology / ErbB Receptors - metabolism / Exosomes / Exosomes - immunology / Exosomes - metabolism / Female / Health aspects / Humans / Immune response / Immunity, Innate - immunology / Immunocompromised Host - immunology / Immunology / Infection / Infectious Diseases / Innate immunity / Interferon / Interferon regulatory factor 3 / Macrophages / Macrophages - immunology / Macrophages - metabolism / Male / MAP Kinase Kinase Kinase 2 - immunology / MAP Kinase Kinase Kinase 2 - metabolism / Medical research / Mice / Mice, Inbred C57BL / Mice, Knockout / Middle Aged / Morbidity / Neoplasms - immunology / Rodents / Translocation / Tumors / Ubiquitin / Ubiquitination / Viral infections / Virus diseases / Virus Diseases - immunology