Tumor-derived exosomes antagonize innate antiviral immunity

被引：200

作者：

Gao, Liang ^{[1
,2
,3
]}

Wang, Lin ^{[3
]}

Dai, Tong ^{[1
,2
,3
]}

Jin, Ke ^{[1
,2
]}

Zhang, Zhengkui ^{[1
,2
]}

Wang, Shuai ^{[3
]}

Xie, Feng ^{[1
,2
,3
]}

Fang, Pengfei ^{[1
,2
]}

Yang, Bing ^{[6
,7
]}

Huang, Huizhe ^{[5
]}

van Dam, Hans ^{[4
]}

Zhou, Fangfang ^{[3
]}

Zhang, Long ^{[1
,2
]}

机构：

[1] Inst Life Sci, Hangzhou, Zhejiang, Peoples R China

[2] Innovat Ctr Cell Signaling Network, Hangzhou, Zhejiang, Peoples R China

[3] Soochow Univ, Inst Biol & Med Sci, Suzhou, Peoples R China

[4] Leiden Univ, Med Ctr, Canc Genom Ctr Netherlands, Dept Mol Cell Biol, Leiden, Netherlands

[5] Chonqing Med Univ, Fac Basic Med Sci, Chongqing, Peoples R China

[6] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA

[7] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA

来源：

NATURE IMMUNOLOGY | 2018年 / 19卷 / 03期

基金：

美国国家科学基金会;

关键词：

NF-KAPPA-B; PATTERN-RECOGNITION RECEPTORS; DOUBLE-STRANDED-RNA; TOLL-LIKE RECEPTOR; RIG-I; T-CELL; TRANSCRIPTION FACTORS; REGULATORY FACTOR-3; CANCER EXOSOMES; PROTEIN;

D O I：

10.1038/s41590-017-0043-5

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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.

引用

页码：233 / +

页数：19

共 53 条

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