Haderk Franziska, Schulz Ralph, Iskar Murat, Cid Laura Llaó, Worst Thomas, Willmund Karolin V, Schulz Angela, Warnken Uwe, Seiler Jana, Benner Axel, Nessling Michelle, Zenz Thorsten, Göbel Maria, Dürig Jan, Diederichs Sven, Paggetti Jérôme, Moussay Etienne, Stilgenbauer Stephan, Zapatka Marc, Lichter Peter, Seiffert Martina
Department of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Signaling and Functional Genomics, DKFZ, Heidelberg, Germany.
Sci Immunol. 2017 Jul 28;2(13). doi: 10.1126/sciimmunol.aah5509.
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.
在慢性淋巴细胞白血病（CLL）中，单核细胞和巨噬细胞倾向于向促肿瘤表型转变，包括释放肿瘤支持性细胞因子以及表达免疫抑制分子，如程序性细胞死亡1配体1（PD-L1）。为了了解驱动CLL中促肿瘤转变的机制，我们评估了肿瘤细胞衍生的外泌体在与单核细胞相互作用中的作用。我们对CLL衍生的外泌体进行了RNA测序和蛋白质组分析，并确定非编码Y RNA hY4是一种高度丰富的RNA种类，与健康供体样本相比，其在CLL患者血浆来源的外泌体中富集。单独将CLL衍生的外泌体或hY4转移至单核细胞会导致关键的CLL相关表型，包括细胞因子的释放，如C-C基序趋化因子配体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）缺陷的单核细胞中消失，提示外泌体hY4是TLR7信号传导的驱动因素。内体TLR信号的药理学抑制导致体外单核细胞活化显著降低，并在体内减弱CLL的发展。我们的结果表明，外泌体介导的非编码RNA向单核细胞的转移通过PD-L1表达促进了癌症相关炎症和同时发生的免疫逃逸。
