Tumour-derived soluble factors induce differentiation of monocytes into M2- polarized macrophages

Macrophage population is generally divided into two distinct subsets: M1 and M2. M1 macrophages act as a first line of defence against pathogens whereas M2 cells participate in wound repair and maintenance of tissue integrity. Within tumor tissues, it has become evident that Tumor-associated macrophages (TAM) have frequently pro-tumor functions. To investigate the role of the tumor micro-environment on macrophage differentiation, we cultured human monocytes with pancreatic cancer cell line supernatants. After 5 days, about 50% of the monocytes differentiated into macrophages in the absence of exogenous cytokine addition. Tumor supernatants did not contain detectable IL-6 or IL-10. The phenotype analysis of tumor-conditioned macrophages (TC-macro) demonstrated high expression of the mannose receptor, CD16, CD68 and low levels of MHC class II. TC-macro produced IL-10, IL-6 and, after LPS stimulation, TNF but not IL-12. Moreover, TC-macro produced a panel of chemokines including CCL2, CXCL8, CCL17 and CXCL10. The transcriptional profile of TC-macro is still under evaluation; several genes in line with an M2 polarization are highly expressed. The nature of the tumor-derived factors inducing macrophage differentiation is currently under investigation. Biochemical studies indicated that the biological activity is excluded from exosomes and have a high molecular weight (>100.000 KDa). A differential proteomic analysis of tumour supernatants from cell lines with and without differentiating ability suggested some proteins as possible candidates. The characterization of tumor-derived factors inducing macrophage differentiation could better clarify the intricate cross-talk between tumor cells and macrophages and thus might aid in the process of devising novel anti-tumor treatments.