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

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.

SUBMITTER: Hirz T

PROVIDER: S-EPMC5641171 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Hirz Taghreed T Matera Eva-Laure EL Chettab Kamel K Jordheim Lars Petter LP Mathé Doriane D Evesque Anne A Esmenjaud Justine J Salles Gilles G Dumontet Charles C

Oncotarget 20170818 42

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 ...[more]

PMID: 29069828

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Project description:BackgroundMechanical ventilation is a life-saving intervention used to provide adequate pulmonary ventilation in patients suffering from respiratory failure. However, prolonged mechanical ventilation is associated with significant diaphragmatic weakness resulting from both myofiber atrophy and contractile dysfunction. Although several signaling pathways contribute to diaphragm weakness during mechanical ventilation, it is established that oxidative stress is required for diaphragmatic weakness to occur. Therefore, identifying the site(s) of mechanical ventilation- induced reactive oxygen species production in the diaphragm is important.ObjectiveThese experiments tested the hypothesis that elevated mitochondrial reactive oxygen species emission is required for mechanical ventilation-induced oxidative stress, atrophy, and contractile dysfunction in the diaphragm.DesignCause and effect was determined by preventing mechanical ventilation-induced mitochondrial reactive oxygen species emission in the diaphragm of rats using a novel mitochondria-targeted antioxidant (SS-31).InterventionsNone.Measurements and main resultsCompared to mechanically ventilated animals treated with saline, animals treated with SS-31 were protected against mechanical ventilation-induced mitochondrial dysfunction, oxidative stress, and protease activation in the diaphragm. Importantly, treatment of animals with the mitochondrial antioxidant also protected the diaphragm against mechanical ventilation-induced myofiber atrophy and contractile dysfunction.ConclusionsThese results reveal that prevention of mechanical ventilation-induced increases in diaphragmatic mitochondrial reactive oxygen species emission protects the diaphragm from mechanical ventilation-induced diaphragmatic weakness. This important new finding indicates that mitochondria are a primary source of reactive oxygen species production in the diaphragm during prolonged mechanical ventilation. These results could lead to the development of a therapeutic intervention to impede mechanical ventilation-induced diaphragmatic weakness.

Dataset Information

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

Publications

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

Similar Datasets

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