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000125347 1001_ $$00000-0001-9658-2778$$aHaderk, Franziska$$b0$$eFirst author
000125347 245__ $$aTumor-derived exosomes modulate PD-L1 expression in monocytes.
000125347 260__ $$aWashington, DC$$bAAAS$$c2017
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000125347 520__ $$aIn chronic lymphocytic leukemia (CLL), monocytes and macrophages are skewed toward protumorigenic phenotypes, including the release of tumor-supportive cytokines and the expression of immunosuppressive molecules such as programmed cell death 1 ligand 1 (PD-L1). To understand the mechanism driving protumorigenic skewing in CLL, we evaluated the role of tumor cell-derived exosomes in the cross-talk with monocytes. We carried out RNA sequencing and proteome analyses of CLL-derived exosomes and identified noncoding Y RNA hY4 as a highly abundant RNA species that is enriched in exosomes from plasma of CLL patients compared with healthy donor samples. Transfer of CLL-derived exosomes or hY4 alone to monocytes resulted in key CLL-associated phenotypes, including the release of cytokines, such as C-C motif chemokine ligand 2 (CCL2), CCL4, and interleukin-6, and the expression of PD-L1. These responses were abolished in Toll-like receptor 7 (TLR7)-deficient monocytes, suggesting exosomal hY4 as a driver of TLR7 signaling. Pharmacologic inhibition of endosomal TLR signaling resulted in a substantially reduced activation of monocytes in vitro and attenuated CLL development in vivo. Our results indicate that exosome-mediated transfer of noncoding RNAs to monocytes contributes to cancer-related inflammation and concurrent immune escape via PD-L1 expression.
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000125347 7001_ $$00000-0002-8594-2050$$aSchulz, Ralph$$b1
000125347 7001_ $$00000-0001-8603-4313$$aIskar, Murat$$b2
000125347 7001_ $$00000-0003-0543-6084$$aCid, Laura Llaó$$b3
000125347 7001_ $$00000-0001-5429-126X$$aWorst, Thomas$$b4
000125347 7001_ $$00000-0002-2935-107X$$aWillmund, Karolin V$$b5
000125347 7001_ $$00000-0002-4491-1581$$aSchulz, Angela$$b6
000125347 7001_ $$00000-0001-9337-1879$$aWarnken, Uwe$$b7
000125347 7001_ $$00000-0002-7633-6278$$aSeiler, Jana$$b8
000125347 7001_ $$00000-0002-7238-6956$$aBenner, Axel$$b9
000125347 7001_ $$00000-0002-0663-4026$$aNessling, Michelle$$b10
000125347 7001_ $$00000-0001-7890-9845$$aZenz, Thorsten$$b11
000125347 7001_ $$aGöbel, Maria$$b12
000125347 7001_ $$aDürig, Jan$$b13
000125347 7001_ $$00000-0001-7901-4752$$aDiederichs, Sven$$b14
000125347 7001_ $$00000-0001-9460-5876$$aPaggetti, Jérôme$$b15
000125347 7001_ $$00000-0002-0879-8067$$aMoussay, Etienne$$b16
000125347 7001_ $$aStilgenbauer, Stephan$$b17
000125347 7001_ $$00000-0001-8287-5967$$aZapatka, Marc$$b18
000125347 7001_ $$00000-0002-2960-5279$$aLichter, Peter$$b19
000125347 7001_ $$00000-0001-5155-663X$$aSeiffert, Martina$$b20$$eLast author
000125347 773__ $$0PERI:(DE-600)2862556-0$$a10.1126/sciimmunol.aah5509$$gVol. 2, no. 13, p. eaah5509 -$$n13$$peaah5509 -$$tScience immunology$$v2$$x2470-9468$$y2017
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