Page 158 - 2019_03-Haematologica-web

Ferrata Storti Foundation
Haematologica 2019 Volume 104(3):564-575
Hodgkin Lymphoma
CCR5 antagonism by maraviroc inhibits Hodgkin lymphoma microenvironment interactions and xenograft growth
Naike Casagrande,1 Cinzia Borghese,1 Lydia Visser,2 Maurizio Mongiat,1 Alfonso Colombatti1 and Donatella Aldinucci1
NC and CB contributed equally to this study.
ABSTRACT
Classic Hodgkin lymphoma tumor cells express a functional CCR5 receptor, and tumor tissues express high CCL5 levels, suggesting that CCL5-CCR5 signaling is involved in tumor-microenviron- ment formation and tumor growth. Using the CCR5 antagonist, maravi- roc, and a neutralizing anti-CCL5 antibody, we found that CCL5 secret- ed by classic Hodgkin lymphoma cells recruited mesenchymal stromal cells and monocytes. The “education” of mesenchymal stromal cells by tumor cell-conditioned medium enhanced mesenchymal stromal cells’ proliferation and CCL5 secretion. In turn, educated mesenchymal stro- mal cell-conditioned medium increased the clonogenic growth of tumor cells and monocyte migration, but these effects were reduced by maravi- roc. Monocyte education by tumor cell-conditioned medium induced their growth and reprogrammed them towards immunosuppressive tumor-associated macrophages that expressed IDO and PD-L1 and secreted IL-10, CCL17 and TGF-b. Educated monocyte-conditioned medium slowed the growth of phytohemagglutinin-activated lympho- cytes. Maraviroc decreased tumor cell growth and synergized with dox- orubicin and brentuximab vedotin. A three-dimensional heterospheroid assay showed that maraviroc counteracted both the formation and via- bility of heterospheroids generated by co-cultivation of tumor cells with mesenchymal stromal cells and monocytes. In mice bearing tumor cell xenografts, maraviroc reduced tumor growth by more than 50% and inhibited monocyte accumulation, without weight loss. Finally, in classic Hodgkin lymphoma human tumor tissues, CCL5 and CD68 expression correlated positively, and patients with high CCL5 levels had poor prog- nosis. In conclusion, since the present challenges are to find molecules counteracting the formation of the immunosuppressive tumor microen- vironment or new, less toxic drug combinations, the repurposed drug maraviroc may represent a new opportunity for classic Hodgkin lym- phoma treatment.
Introduction
Inflammatory chemokines are indispensable “gate-keepers” of inflammation and immunity against cancer, but tumor cells can subvert chemokines into acting as tumor-promoting molecules.1 C-C motif chemokine ligand 5 (CCL5) is one such chemokine that can favor tumor development in multiple ways; for example, by acting as a growth factor for tumor cells, stimulating angiogenesis, recruiting stro- mal and inflammatory cells, and taking part in immune evasion mechanisms.2-6 CCL5 belongs to the C-C chemokine family whose members include CCL3 and CCL4.1,2 Its activity is mediated through binding to CCR1, CCR3, and CCR5, while CD44 serves as an auxiliary receptor.2
CCL5 and other chemokines are expressed at higher levels in classic Hodgkin lymphoma (cHL) tumor tissues than in healthy lymph nodes and in tissues with
1Unit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy and 2Department of Pathology and Medical Biology, University Medical Center Groningen (UMcG), the Netherlands
Correspondence:
DONATELLA ALDINUCCI
daldinucci@cro.it
Received: May 3, 2018. Accepted: October 9, 2018. Pre-published: October 11, 2018.
doi:10.3324/haematol.2018.196725
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/3/564
©2019 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
564
haematologica | 2019; 104(3)
ARTICLE