Targeting dormant disseminated tumor cells and their permissive niche by pro-resolving mediators derived from resolution-phase macrophages

Metastatic breast cancer (BC) can recur years after initial treatments and arise from quiescent disseminated tumor cells (QDTC) that resist conventional therapies. To date there are no treatments to target QDTCs. Previously, the fibrotic-like niche (FLN) enriched with Type I collagen (Col-I) was shown to be required for the switch of QDTC to overt metastases. Here, we examined whether artificially reinstating resolution of inflammation, by using soluble mediators secreted by ex-vivo generated pro-resolving macrophages (CM-Mres), will prevent FLN establishment and in turn hinder QDTC outgrowth. Our findings indicate that CM-Mres promoted immune silencing at the metastatic site as part of the resolution process and inhibited the FLN resulting in the inhibition of the metastatic outgrowth in vitro and in vivo. This was due to inhibition of fibroblasts to myofibroblasts differentiation independent of TGFβ1 canonical signaling and the abolishment of Col-I expression. Furthermore, CM-Mres eliminated myofibroblasts as part of the resolution process by inducing an increase in reactive oxygen species (ROS) via NADPH oxidase leading to DNA damage and apoptosis. Moreover, ROS–mediated apoptosis was also induced by CM-Mres in the dormant and outgrowing DTCs. Overall, our findings suggest for the first time that pro-resolving mediators can target both QDTCs and their permissive niche thus preventing BC from recurring. Significance: Since conventional therapies fail to eradicate QDTCs. Future identification of the pro-resolving mediators secreted by pro-resolving macrophages may serve as a basis for novel therapeutic strategies targeting QDTCs and their metastatic niche.