Abstract 398: Tumor microenvironment imposes major alterations and profoundly shapes functional status of macrophages: peritoneal and tumor-associated macrophages from tumor hosts are two very different subpopulations

Abstract

Abstract Macrophages are key players in the inflammatory response and exhibit significant roles in the different stages of tumor progression. We have previously reported deficient functions of peritoneal macrophages of D1-DMBA3 mammary tumors bearers (T-PEMs). We showed that T-PEMs are impaired in inflammatory activity due to diminished expression of transcription factors NFκB and C/EBP. We have also demonstrated that T-PEMs display neither M1 nor M2 phenotypes, exhibit deficiencies in the production of several inflammatory cytokines, are less differentiated and show increased apoptosis. Importantly, we showed for the first time that their apoptosis in periphery contributes to increased myelopoiesis. We examined the blood monocytes from these tumor mice and demonstrated that these cells are neither inflammatory nor suppressive and are less differentiated, similar to the T-PEMs they later become. In the present study we investigate tumor-associated macrophages (TAMs) from the same tumor model and compare them with T-PEMs and with peritoneal macrophages from normal mice (N-PEMs). Our results show that TAMs downregulate IL-12p70, but upregulate IL-12p40, IL-23, IL-6 and IL-10 and chemokines and their receptors are very differently expressed in these two macrophages subpopulations. NFκB and C/EBP family members are decreased in TAMs as compared with T-PEMs, however NFκBp50 homodimers, STAT1/pSTAT1 and STAT3/pSTAT3 are all overexpressed. Moreover TAMs block T-cell proliferation and are more prone to apoptosis than T-PEMs due to a higher expression of activated caspase-3 and downregulation of Bcl-X. Our results show that T-PEMs and TAMs have equally impaired phagocytic capacity compared with fully-phagocytic N-PEMs. Moreover, TAMs constitutively express iNOS, produce nitric oxide but no arginase and are Gr-1high and CD11blow, thus are not classic myeloid-derived suppressor cells. Collectively, our results show that the exposure to different locations and tumor factor gradients determine macrophage phenotypes and functions. The tumor microenvironment, as the setting in most intimate contact with tumor cells is the one that most alters macrophage activity. Targeting tumor factors and other cells in the tumor microenvironment may allow reversion of macrophage dysfunction. 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 398. doi:1538-7445.AM2012-398