Tumor-derived exosomes modulate PD-L1 expression in monocytes
Tumor-derived exosomes modulate PD-L1 expression in monocytes
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DOI：
10.1126/sciimmunol.aah5509
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发表时间：
2017-07-01
影响因子：
24.8
通讯作者：
Seiffert, Martina
中科院分区：
文献类型：
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作者：
Haderk, Franziska;Schulz, Ralph;Seiffert, Martina
在慢性淋巴细胞白血病（CLL）中，单核细胞和巨噬细胞倾向于致瘤表型，包括肿瘤支持细胞因子的释放和免疫抑制分子如程序性细胞死亡1配体1 （PD-L1）的表达。为了了解CLL中驱动蛋白原性偏斜的机制，我们评估了肿瘤细胞来源的外泌体在与单核细胞的串扰中的作用。我们对CLL衍生的外泌体进行了RNA测序和蛋白质组分析，发现非编码Y RNA hY4是一种高度丰富的RNA，与健康供体样本相比，CLL患者血浆外泌体中富集了这种RNA。cll衍生的外泌体或hY4单独转移到单核细胞导致关键的cll相关表型，包括细胞因子的释放，如C-C基元趋化因子配体2 （CCL2）、CCL4和白细胞介素6，以及PD-L1的表达。这些反应在toll样受体7 （TLR7）缺陷的单核细胞中被消除，表明外泌体hY4是TLR7信号传导的驱动因素。内体TLR信号的药理抑制导致体外单核细胞的激活大大降低，体内CLL的发展减弱。我们的研究结果表明，外泌体介导的非编码rna向单核细胞的转移有助于癌症相关炎症和通过PD-L1表达的同步免疫逃逸。
In chronic lymphocytic leukemia (CLL), monocytes and macrophages are skewed toward protumorigenic phenotypes, including the release of tumor-supportive cytokines and the expression of immunosuppressive molecules such as programmed cell death 1 ligand 1 (PD-L1). To understand the mechanism driving protumorigenic skewing in CLL, we evaluated the role of tumor cell-derived exosomes in the cross-talk with monocytes. We carried out RNA sequencing and proteome analyses of CLL-derived exosomes and identified noncoding Y RNA hY4 as a highly abundant RNA species that is enriched in exosomes from plasma of CLL patients compared with healthy donor samples. Transfer of CLL-derived exosomes or hY4 alone to monocytes resulted in key CLL-associated phenotypes, including the release of cytokines, such as C-C motif chemokine ligand 2 (CCL2), CCL4, and interleukin-6, and the expression of PD-L1. These responses were abolished in Toll-like receptor 7 (TLR7)-deficient monocytes, suggesting exosomal hY4 as a driver of TLR7 signaling. Pharmacologic inhibition of endosomal TLR signaling resulted in a substantially reduced activation of monocytes in vitro and attenuated CLL development in vivo. Our results indicate that exosome-mediated transfer of noncoding RNAs to monocytes contributes to cancer-related inflammation and concurrent immune escape via PD-L1 expression.