TY  - JOUR
AU  - Haderk, Franziska
AU  - Schulz, Ralph
AU  - Iskar, Murat
AU  - Cid, Laura Llaó
AU  - Worst, Thomas
AU  - Willmund, Karolin V
AU  - Schulz, Angela
AU  - Warnken, Uwe
AU  - Seiler, Jana
AU  - Benner, Axel
AU  - Nessling, Michelle
AU  - Zenz, Thorsten
AU  - Göbel, Maria
AU  - Dürig, Jan
AU  - Diederichs, Sven
AU  - Paggetti, Jérôme
AU  - Moussay, Etienne
AU  - Stilgenbauer, Stephan
AU  - Zapatka, Marc
AU  - Lichter, Peter
AU  - Seiffert, Martina
TI  - Tumor-derived exosomes modulate PD-L1 expression in monocytes.
JO  - Science immunology
VL  - 2
IS  - 13
SN  - 2470-9468
CY  - Washington, DC
PB  - AAAS
M1  - DKFZ-2017-01480
SP  - eaah5509 -
PY  - 2017
N1  - Science Immunology (Sci. Immunol.) = 2470-9468 (import from CrossRef, PubMed, )
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:28754746
DO  - DOI:10.1126/sciimmunol.aah5509
UR  - https://inrepo02.dkfz.de/record/125347
ER  -