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Oncotarget. 2017 Aug 18;8(42):72818-72834. doi: 10.18632/oncotarget.20350. eCollection 2017 Sep 22.

Neutrophils protect lymphoma cells against cytotoxic and targeted therapies through CD11b/ICAM-1 binding.

Author information

1
Anticancer Antibody Team, INSERM U1052, CNRS UMR 5286, Cancer Research Center of Lyon, University of Lyon, Lyon, France.
2
Hospices Civils de Lyon, Department of Hematology, Pierre-Benite, France.
3
Université Claude Bernard Lyon-1, Lyon, France.
4
ProfileXpert, Lyon, France.
5
Laboratory of Hematology, Hospices Civils de Lyon, Pierre-Bénite, France.

Abstract

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.

KEYWORDS:

cell-cell interactions; chemotherapy; lymphoma; neutrophils; targeted therapy

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.

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