Oncotarget

Research Papers:

Ibrutinib modifies the function of monocyte/macrophage population in chronic lymphocytic leukemia

Stefania Fiorcari, Rossana Maffei, Valentina Audrito, Silvia Martinelli, Elisa Ten Hacken, Patrizia Zucchini, Giulia Grisendi, Leonardo Potenza, Mario Luppi, Jan A. Burger, Silvia Deaglio and Roberto Marasca _

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Oncotarget. 2016; 7:65968-65981. https://doi.org/10.18632/oncotarget.11782

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Abstract

Stefania Fiorcari1,*, Rossana Maffei1,*, Valentina Audrito2, Silvia Martinelli1, Elisa ten Hacken3, Patrizia Zucchini1, Giulia Grisendi1, Leonardo Potenza1, Mario Luppi1, Jan A. Burger3, Silvia Deaglio2, Roberto Marasca1

1Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy

2Department of Medical Sciences, University of Turin and Human Genetics Foundation, Turin, Italy

3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

*These authors have contributed equally to this work

Correspondence to:

Roberto Marasca, email: roberto.marasca@unimore.it

Stefania Fiorcari, email: stefania.fiorcari@unimore.it

Keywords: CLL, ibrutinib, microenvironment, nurse-like cells, immune modulation

Received: June 08, 2016    Accepted: August 15, 2016    Published: September 01, 2016

ABSTRACT

In lymphoid organs, nurse-like cells (NLCs) show properties of tumor-associated macrophages, playing a crucial role in chronic lymphocytic leukemia (CLL) cell survival. Ibrutinib, a potent inhibitor of Bruton’s tyrosine kinase (BTK), is able to counteract pro-survival signals in CLL cells. Since the effects on CLL cells have been studied in the last years, less is known about the influence of ibrutinib on NLCs properties. We sought to determine how ibrutinib modifies NLCs functions focusing on the balance between immunosuppressive and inflammatory features. Our data show that ibrutinib targets BTK expressed by NLCs modifying their phenotype and function. Treatment with ibrutinib reduces the phagocytic ability and increases the immunosuppressive profile of NLCs exacerbating the expression of M2 markers. Accordingly, ibrutinib hampers LPS-mediated signaling, decreasing STAT1 phosphorylation, while allows IL-4-mediated STAT6 phosphorylation. In addition, NLCs treated with ibrutinib are able to protect CLL cells from drug-induced apoptosis partially through the secretion of IL-10. Results from patient samples obtained prior and after 1 month of treatment with ibrutinib show an accentuation of CD206, CD11b and Tie2 in the monocytic population in the peripheral blood. Our study provides new insights into the immunomodulatory action of ibrutinib on monocyte/macrophage population in CLL.


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