MSCs Induces Immunosuppressive Neutrophils To Promote Tumor Progression

Introduction: Accumulating evidences indicates a critical role of neutrophils inthe pathophysiology of different types of cancer. Increased numbers of neutrophilsobtain suppressive function during tumor development, yet the mechanisms arepoorly understood. Therefore,it is necessary to study the mechanisms modulating thefunction of neutrophils in the context of mesenchymal stem cells (MSCs), the keycomponents of tumor microenvironment.Methods: Bone marrow-derived MSCs were isolated from Balb/c mice,andcharacterized by surface markers. Suppressive Function of neutrophils was evaluatedby anti-CD3stimulated T cell proliferation assay and4T1breast tumor model, Themolecular mechanisms were explored by transcriptional profiling, real time RT-PCR,and arginase activity measurement.Results: Co-cultured with MSCs significantly inhibited apoptosis of restingbone marrow neutrophils and zymosan A induced neutrophils. After coculture bonemarrow neutrophils could inhibit anti-CD3stimulated T cells proliferation in vitro. Invivo experiments showed that MSCs-treated neutrophils could promote4T1tumorprogression. Mechanistically, TNF-α-MSCs induced expression of iNOS、 saa3,inhibitory cytokines and their receptors (IL-10, IL-10R), chemokines and relativereceptors, and increased arginase1activity.These changes might mediate the effect ofneutrophils to inhibit T cell activation and proliferation, and thereby enhance tumorprogression.Conclusion: Our study suggested that MSCs could program neutrophils into animmunosuppressive phenotype and these cells might have important tumor-promotingactivities.