Neutrophils with protumor potential could efficiently suppress tumor growth after cytokine priming and in presence of normal NK cells

In tumor-bearing state, the function of neutrophils is converted from tumor-suppressing to tumor-promoting. Here we report that priming with IFN-gamma and TNF-alpha could convert the potential of neutrophils from tumor-promoting to tumor-suppressing. The neutrophils with protumor potential have not lost their responsiveness to IFN-gamma and TNF-alpha. After priming with IFN-gamma and TNF-alpha, the potential of the neutrophils to express Bv8 and Mmp9 genes was reduced. Conversely, the tumor-promotional neutrophils recovered the expression of Rab27a and Trail, resumed the activation levels of PI3K and p38 MAPK pathways in response to stimuli, and expressed higher levels of IL-18 and NK-activating ligands such as RAE-1, MULT-1, and H60. Therefore, the anti-tumor function of the neutrophils was augmented, including the cytotoxicity to tumor cells, the capability of degranulation, and the capacity to activate NK cells. Since the function of NK cells is impaired in tumor-bearing state, the administration of normal NK cells could significantly augment the efficiency of tumor therapy based on neutrophil priming. These findings highlight the reversibility of neutrophil function in tumor-bearing state, and suggest that neutrophil priming by IFN-gamma/TNF-alpha might be a potential approach to eliminate residual tumor cells in comprehensive strategy for tumor therapy.