Shen et al. identified a paracrine feedback loop in which macrophage-derived TGFβ activates Notch in tumor cells which, in turn, primes the tumor cell to respond to TGFβ, and further promotes uPA-dependent production of TGFβ by mature macrophages. These macrophages also produce Notch-dependent cytokines IL1β and CCL2, which promote monocyte recruitment and infiltration, as well as tumor progression.
Notch activation, which is associated with basal-like breast cancer (BLBC), normally directs tissue patterning, suggesting that it may shape the tumor microenvironment (TME). Here we show that Notch in tumor cells regulates the expression of two powerful pro-inflammatory cytokines, IL1beta and CCL2, and the recruitment of tumor-associated macrophages (TAMs). Notch also regulates TGFbeta-mediated activation of tumor cells by TAMs, closing a Notch-dependent paracrine signaling loop between these two cell types. We use a novel mouse model in which Notch can be regulated in spontaneous mammary carcinoma to confirm that IL1beta and CCL2 production, and macrophage recruitment are Notch-dependent. In human disease, expression array analyses demonstrate a striking association between Notch activation, IL1beta and CCL2 production, macrophage infiltration and BLBC. These findings place Notch at the nexus of a vicious cycle of macrophage infiltration and amplified cytokine secretion and provide novel immunotherapeutic opportunities in BLBC.