Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function

被引:392
作者
Liu, CR
Yu, SH
Zinn, K
Wang, JH
Zhang, LM
Jia, YJ
Kappes, JC
Barnes, S
Kimberly, RP
Grizzle, WE
Zhang, HG
机构
[1] Univ Alabama Birmingham, Div Clin Immunol & Rheumatol, Dept Med, Birmingham, AL 35294 USA
[2] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA
[3] Univ Alabama Birmingham, Dept Pharmacol, Birmingham, AL 35294 USA
[4] Univ Alabama Birmingham, Dept Radiat Oncol, Birmingham, AL 35294 USA
[5] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA
[6] Birmingham Vet Adm Med Ctr, Birmingham, AL 35233 USA
关键词
D O I
10.4049/jimmunol.176.3.1375
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Many tumor cells shed specialized membrane vesicles known as exosomes. In this study, we show that pretreatment of mice with exosomes produced by TS/A or 4T.1 murine mammary tumor cells resulted in accelerated growth of implanted tumor cells in both syngeneic BALB/c mice and nude mice. As implanted TS/A tumor cells grew more rapidly in mice that had been depleted of NK cells, we analyzed the effects of the tumor-derived exosomes on NK cells. The tumor-derived exosomes inhibit NK cell cytotoxic activity ex vivo and in vitro as demonstrated by chromium release assays. The treatment of mice with TS/A tumor exosomes also led to a reduction in the percentages of NK cells, as determined by FACS analysis, in the lungs and spleens. Key features of NK cell activity were inhibited, including release of perforin but not granzyme B, as well as the expression of cyclin D3 and activation of the Jak3-mediated pathways. Human tumor cell lines also were found to produce exosomes that were capable of inhibiting IL-2-stimulated NK cell proliferation. Exosomes produced by dendritic cells or B cells did not. The presentation of tumor Ags by exosomes is under consideration as a cancer vaccine strategy; however, we found that pretreatment of mice with tumor exosomes blunted the protective effect of syngeneic dendritic cells pulsed ex vivo with tumor exosomes. We propose that tumor exosomes contribute to the growth of tumors by blocking IL-2-mediated activation of NK cells and their cytotoxic response to tumor cells.
引用
收藏
页码:1375 / 1385
页数:11
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