Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human

The importance of tumor associated neutrophils (TANs) in cancer development is in the meantime well established. Numerous of clinical data document the adverse prognostic effects of neutrophil infiltration in solid tumors. However, certain tumor therapies need functional neutrophils to be effective, suggesting altered neutrophil polarization associated with different outcomes for cancer patients. Therefore, modulation of neutrophilic phenotypes represents a potent therapeutic option, but factors mediating neutrophil polarization are still poorly defined. In this manuscript we provide evidence that type I IFNs alter neutrophilic phenotype into anti-tumor, both in mice and human. In the absence of IFN-, pro-tumor properties, such as reduced tumor cytotoxicity with low neutrophil extracellular traps (NETs) expression, low ICAM1 and TNF- expression, dominated neutrophil phenotypes in primary lesion and premetastatic lung. Interestingly, such neutrophils have significantly prolonged life-span. Notably, interferon therapy in mice altered TAN polarization towards anti-tumor N1. Similar changes in neutrophil activation could be observed in melanoma patients undergoing type I IFN therapy. Altogether, these data highlight the therapeutic potential of interferons, suggesting optimization of its clinical use as potent anti-tumor agent. What's new? Tumor-associated neutrophils (TANs) can act in ways that seem to be contradictory. When they're in N1 mode, they release factors that inhibit tumor growth and metastasis, while N2 mode is pro-tumor. Cytokines appear to influence which role TANs will play. In this study, the authors found that type I interferons can activate, or polarize, TANs into the anti-tumor N1 phenotype, in both mice and in human cancer patients. The authors then analyzed the molecular mechanisms involved. Their findings indicate that type I IFNs may have significant therapeutic potential.