Neutrophils protect lymphoma cells against cytotoxic and targeted therapies through CD11b/ICAM-1 binding
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Taghreed Hirz1, Eva-Laure Matera1, Kamel Chettab1, Lars Petter Jordheim1, Doriane Mathé1, Anne Evesque1, Justine Esmenjaud1, Gilles Salles2,3 and Charles Dumontet1,4,5
1Anticancer Antibody Team, INSERM U1052, CNRS UMR 5286, Cancer Research Center of Lyon, University of Lyon, Lyon, France
2Hospices Civils de Lyon, Department of Hematology, Pierre-Benite, France
3Université Claude Bernard Lyon-1, Lyon, France
4ProfileXpert, Lyon, France
5Laboratory of Hematology, Hospices Civils de Lyon, Pierre-Bénite, France
Charles Dumontet, email: [email protected]
Keywords: neutrophils, lymphoma, chemotherapy, targeted therapy, cell-cell interactions
Received: April 11, 2017 Accepted: July 14, 2017 Published: August 18, 2017
Innate immune cells constitute a substantial proportion of the cells within the tumor microenvironment. Besides the contribution of the microenvironment to tumor proliferation and survival, there is direct evidence that interactions between tumor cells and their microenvironment alter sensitivity to anti-cancer agents. Neutrophils, a key player in the innate immune system, have been less studied than many other immune cells regarding their impact on cancer cell response to anti-cancer agents. In our 2D and 3D coculture systems, human neutrophils and differentiated HL60 cells attenuated the sensitivity of various lymphoma cell lines to several anti-cancer agents, including targeted therapies. Neutrophil-induced protection was dependent on cell-cell interaction between CD11b and ICAM-1 expressed by neutrophils and B cells, respectively and was shown to be Mcl-1-dependent. The protective effect of neutrophils was validated in vivo using immune-compromised mice inoculated with human NHL with our without neutrophils then followed by treatment with chemotherapy. Similar findings were made on primary cells purified from patients with chronic lymphocytic leukemia, treated with fludarabine or targeted agents in the presence of autologous neutrophils. In a clinical study, patients with non-Hodgkin’s lymphoma with increased neutrophil counts displayed a reduced response rate to therapy. These findings reveal a novel protective mechanism of neoplastic B cells involving innate immune cells which could be pharmacologically targeted to enhance the antitumor effect of therapy.
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