Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/37511
Title: Extracellular vesicles released by CD40/IL-4 stimulated chronic lymphocytic leukemia cells confer altered functional properties to CD4+ T cells
Authors: Smallwood, Dawn T.
Apollonio, Benedetta
Willimott, Shaun
Lezina, Larissa
Alharthi, Afaf
Ambrose, Ashley R.
De Rossi, Giulia
Ramsay, Alan G.
Wagner, Simon D.
First Published: 26-Apr-2016
Publisher: American Society of Hematology
Citation: Blood, 2016, 128 (4), pp. 542-552
Abstract: The complex interplay between cancer cells, stromal cells and immune cells in the tumor microenvironment (TME) regulates tumorigenesis and provides emerging targets for immunotherapies. Crosstalk between CD4(+) T cells and proliferating chronic lymphocytic leukemia (CLL) tumor B cells occurs within lymphoid tissue pseudo-follicles and investigating these interactions is essential to understand both disease pathogenesis and the effects of immunotherapy. Tumor-derived extracellular vesicle (EV) shedding is emerging as an important mode of intercellular communication in the TME. In order to characterize tumor EVs released in response to T cell-derived TME signals, we performed microRNA (miR) profiling of EVs released from CLL cells stimulated with CD40 and IL-4. Our results reveal an enrichment of specific cellular miRNAs including miR-363 within EVs derived from CD40/IL-4 stimulated CLL cells compared to parental cell miRNA content and control EVs from unstimulated CLL cells. We demonstrate that autologous patient CD4(+) T cells internalize CLL-EVs containing miR-363 that targets the immunomodulatory molecule CD69. We further reveal that autologous CD4(+) T cells that are exposed to EVs from CD40/IL-4 stimulated CLL cells exhibit enhanced migration, immunological synapse signaling and interactions with tumor cells. Knockdown of miR-363 in CLL cells prior to CD40/IL-4 stimulation, prevented the ability of CLL-EVs to induce increased synapse signaling and confer altered functional properties to CD4(+) T cells. Taken together, these data reveal a novel role for CLL-EVs in modifying T cell function that highlights unanticipated complexity of intercellular communication that may have implications for bidirectional CD4(+) T-cell:tumor interactions within the TME.
DOI Link: 10.1182/blood-2015-11-682377
eISSN: 1528-0020
Links: http://www.bloodjournal.org/content/early/2016/04/26/blood-2015-11-682377?sso-checked=true
http://hdl.handle.net/2381/37511
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2016. This version is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

Files in This Item:
File Description SizeFormat 
addl_pappdf9993088.pdfPost-review (final submitted)2.17 MBAdobe PDFView/Open


Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.