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

July 28, 2017 By:
  • Haderk F
  • Schulz R
  • Iskar M
  • Cid LL
  • Worst T
  • Willmund KV
  • Schulz A
  • Warnken U
  • Seiler J
  • Benner A
  • Nessling M
  • Zenz T
  • Gobel M
  • Durig J
  • Diederichs S
  • Paggetti J
  • Moussay E
  • Stilgenbauer S
  • Zapatka M
  • Lichter P
  • Seiffert M.

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.

2017 Jul. Sci Immunol.2(13):pii: eaah5509.
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