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Sci Immunol. 2017 Jul 28;2(13). pii: eaah5509. doi: 10.1126/sciimmunol.aah5509.

Tumor-derived exosomes modulate PD-L1 expression in monocytes.

Author information

1
Department of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Division of Signaling and Functional Genomics, DKFZ, Heidelberg, Germany.
3
Genomics and Proteomics Core Facility, DKFZ, Heidelberg, Germany.
4
Division of RNA Biology and Cancer (B150), DKFZ, Heidelberg, Germany.
5
Division of Biostatistics, DKFZ, Heidelberg, Germany.
6
Central Unit Electron Microscopy, DKFZ, Heidelberg, Germany.
7
Department of Molecular Therapy in Hematology and Oncology and Department of Translational Oncology, National Center for Tumor Diseases (NCT); DKFZ; and Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
8
Department of Hematology, Essen University Hospital, Essen, Germany.
9
Division of Cancer Research, Department of Thoracic Surgery, Medical Center-Faculty of Medicine, University of Freiburg, Freiburg, Germany.
10
German Cancer Consortium (DKTK), Freiburg, Germany.
11
Laboratory of Experimental Cancer Research, Luxembourg Institute of Health, Luxembourg City, Luxembourg.
12
Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany.
13
Department of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany. m.seiffert@dkfz.de.

Abstract

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.

PMID:
28754746
DOI:
10.1126/sciimmunol.aah5509

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