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* Laboratory of Cellular and Gene Therapy "G. Lanzani," Division of Haematology, Ospedali Riuniti di Bergamo, Bergamo, Italy;
Department of Pathology, University of Milan School of Medicine and Humanitas Clinical Institute Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano, Milan, Italy;
Department of Inflammation and Immunology, Fondazione Humanitas per la Ricerca, Rozzano, Milan, Italy; and
Division of Hematology, Ospedale Ferrarotto, Catania, Italy
Because macrophages have been implicated as major players in the mechanism of action of rituximab, we have investigated the factors that modulate their tumor cell killing potential. Human macrophages, differentiated in vitro from peripheral blood monocytes, were used in binding and phagocytosis assays using B-chronic lymphocytic leukemia or lymphoma target cells opsonized with rituximab. Phagocytosis was maximal at 0.1 µg/ml rituximab and was not significantly affected by CD20 expression levels or by CD16A polymorphism at position 158 (Val/Phe). The role of Fc
Rs was demonstrated by complete inhibition of phagocytosis by excess human Igs. Because macrophages can be differentiated to M1- or M2-type cells with either GM-CSF or M-CSF, respectively, and can be classically activated by proinflammatory stimuli (IFN-/LPS) or undergo alternative activation with cytokines such as IL-4 or IL-10, we have analyzed the effect of these different polarization programs on the phagocytosis mediated by rituximab. Macrophages differentiated in presence of M-CSF showed a 2- to 3-fold greater phagocytic capacity compared with GM-CSF-induced cells. Furthermore, addition of IL-10 significantly increased, whereas IL-4 decreased phagocytosis by both M-CSF- and GM-CSF-differentiated macrophages. LPS/IFN- had little effect. Expression of CD16, CD32, and CD64 in different macrophage populations correlated with phagocytic activity. Interestingly, several B lymphoma cell lines were observed to secrete 400-1300 pg/ml IL-10 in vitro, and coculture of human macrophages with lymphoma conditioned medium increased significantly their phagocytic capacity. Our data suggest that cytokines secreted by lymphoma cells can favor alternate activation of macrophages with a high phagocytic capacity toward rituximab-opsonized targets.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Italian Association for Cancer Research (AIRC), the Associazione Italiana contro le Leucemia, Linfomi e Mieloma (AIL)-Sezione Paolo Belli, the European Commission (Specific Targeted Research Project "Bispecific Monoclonal Antibody Technology Concept," BMC), and Roche Italia.
2 Address correspondence and reprint requests to Dr. Josée Golay, Laboratory of Cellular and Gene Therapy "G. Lanzani," c/o Presidio Matteo Rota, via Garibaldi 11-13, Ospedali Riuniti di Bergamo, 24128 Bergamo, Italy. E-mail address: jgolay{at}ospedaliriuniti.bergamo.it
3 Abbreviations used in this paper: B-CLL, B-chronic lymphocytic leukemia; ADCC, Ab-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; M1, type I macrophage; M2, type II macrophage; MCL, mantle cell lymphoma; MFI, mean fluorescence intensity; TAM, tumor-associated macrophage.
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