Abstract 402: Plasticity of tumor associated macrophages in a metastatic melanoma model in the mouse

Abstract

Abstract Macrophages acquire different functional traits, with the pro-inflammatory, classically activated M1 and the tissue-repair, alternatively activated M2 phenotypes the best characterized to date. Tumor-associated macrophages (TAMs) have been described as alternatively activated and exert pro-tumoral activity. We investigated TAMs isolated from subcutaneous tumors and experimental lung metastases at an early (72 h) and late (3 wk) stage within a B16F10 mouse melanoma model. The macrophages were characterized according to their expression of genes, surface markers and secreted factors. Interestingly, the mRNA profile revealed both M1- and M2-associated gene expression in macrophages derived from s.c. melanoma, including Cxcl9, Cxcl11, Il-1a, Nos2, and Retnla (FIZZ-1), Arg-1 and Fn1, respectively. In early pulmonary metastases, we found that macrophages also expressed both pro-inflammatory (Il1b, Il12b, Ccl2), and anti-inflammatory (Ccl17 and Ccl22) cytokines and chemokines and other M1- and M2-associated genes, such as Cd40, Cd86, and Il27ra and Itgax (Cdd11c), respectively. Macrophages from late stage lung metastases displayed predominantly alternatively activated characteristics with Arg1, Retnla and Fn1 expression, but pro-inflammatory genes, such as Ccl2, Il1b and Cxcl10 were also induced/upregulated. We therefore suggest an intermediate phenotype of TAMs which does not fit the orthodox M1/M2 paradigm. To describe the mechanism by which macrophages are recruited to pulmonary metastases, we investigated chemokine receptor expression of macrophages infiltrating the lung. While Ccr2 was expressed at high level in macrophages associated with both the control and B16F10 metastases bearing lung, we found that Ccr1 and Ccr5 expression was induced after tumor cell challenge. The secretion profile of B16F10 cells revealed CCL5 (RANTES), a ligand for these receptors, secreted at high level, which suggests that CCL5 attracts macrophages to lung metastases via CCR1 and CCR5. The effect of anti-CCL5 antibody treatment, and s.c melanoma growth and pulmonary metastasis development in CCR1-/- and CCR5-/- mice will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 402. doi:1538-7445.AM2012-402