%0 Journal Article
%A Haderk, Franziska
%A Schulz, Ralph
%A Iskar, Murat
%A Cid, Laura Llaó
%A Worst, Thomas
%A Willmund, Karolin V
%A Schulz, Angela
%A Warnken, Uwe
%A Seiler, Jana
%A Benner, Axel
%A Nessling, Michelle
%A Zenz, Thorsten
%A Göbel, Maria
%A Dürig, Jan
%A Diederichs, Sven
%A Paggetti, Jérôme
%A Moussay, Etienne
%A Stilgenbauer, Stephan
%A Zapatka, Marc
%A Lichter, Peter
%A Seiffert, Martina
%T Tumor-derived exosomes modulate PD-L1 expression in monocytes.
%J Science immunology
%V 2
%N 13
%@ 2470-9468
%C Washington, DC
%I AAAS
%M DKFZ-2017-01480
%P eaah5509 -
%D 2017
%Z Science Immunology (Sci. Immunol.) = 2470-9468 (import from CrossRef, PubMed, )
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:28754746
%R 10.1126/sciimmunol.aah5509
%U https://inrepo02.dkfz.de/record/125347