Tumor-derived exosomes modulate PD-L1 expression in monocytes.
Haderk, Franziska 1; Schulz, Ralph 1; Iskar, Murat 1; Cid, Laura Llao 1; Worst, Thomas 2; Willmund, Karolin V. 1; Schulz, Angela 1,3; Warnken, Uwe 3; Seiler, Jana 4; Benner, Axel 5; Nessling, Michelle 6; Zenz, Thorsten 7; Gobel, Maria 8; Durig, Jan 8; Diederichs, Sven 4,9,10; Paggetti, Jerome 11; Moussay, Etienne 11; Stilgenbauer, Stephan 12; Zapatka, Marc 1; Lichter, Peter 1; Seiffert, Martina 1,*
[Article]
Science Immunology.
2(13), July 28, 2017.
(Format: HTML, PDF)
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.
Copyright (C) 2017 by the American Association for the Advancement of Science
