mTOR is essential for neutrophil polarization by TGF-β

Several lines of evidence suggest that the TGF-β family is involved in tumor initiation and progression. TGF-β acts on distinct elements of the tumor microenvironment, suppresses immune surveillance, promotes angiogenesis and activates cancer-associated fibroblasts that will further contribute to metastasis. TGF-β signaling can be activated by both the canonical Smad-dependent, and non-canonical signalling pathways such as ERK1/2, JNK1/2, and mTOR. TGF-β has been shown to block neutrophil anti tumor cytotoxicity and drive neutrophils towards a pro-tumor phenotype. However, the pathway(s) that are involved in this transition are unknown. Here, we show that neutrophil specific inhibition of the mTOR pathway is sufficient to block the inhibitory effect of TGF-β on neutrophil anti tumor cytotoxicity. Conversely, activation of mTOR signaling in neutrophils is sufficient to block neutrophil cytotoxicity. These data suggest that manipulating mTOR signaling in neutrophils in vivo may potentiate their anti tumor properties and limit tumor progression.