Blockade of CC chemokine receptor 2 suppresses pancreatic cancer progression through the interaction with macrophages in the tumor microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is the most intractable cancer, demonstrating abundant stroma in the tumor microenvironment (TME). Previously, we reported that CXC chemokines contributed to the progression of PDAC through tumor-stromal interaction. Since CC chemokines were also highly expressed in the TME, we hypothesized that the CC chemokine signaling promotes PDAC progression. CC chemokine receptor 2 (CCR2) was primarily expressed in macrophages in the murine PDAC tissues, therefore, we investigated the role of CCR2 in the interaction between macrophages and PDAC cells. Macrophages significantly induced PDAC cell invasion in vitro, whereas, the induction was canceled by Ccr2-knockout (KO) macrophages. CXC chemokines, differentially expressed between wild-type and Ccr2 KO macrophages, contributed to the PDAC invasion. Systemic Ccr2 KO significantly prolonged the survival of autochthonous PDAC mice, demonstrating a shift of macrophage composition, decrease of Arginase-1+ and increase of iNOS+ macrophages, and decrease of PDAC microinvasion, as well as increase of PDAC apoptosis. PDAC cells stimulated by Ccr2 KO macrophages showed activated interferon-α (Ifn-α)-STAT1 signaling, while Ccr2 KO upregulated Ifn-α expression, thereby directly inducing PDAC cell apoptosis. These results elucidated the pivotal role of CCR2 in PDAC progression and inhibition through the interaction of macrophages and PDAC cells in the TME.