Abstract 3816: Blood monocytes from tumor-bearing mice exhibit a mixture of inflammatory and anti-inflammatory genes and downregulate differentiation markers

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Abstract Inflammation and immune suppression are two opposing immune responses linked in different ways to cancer: earlier stages of tumor development are associated with chronic inflammation, while established cancers induce immune suppression. Macrophages are key players of the inflammatory response and exhibit significant roles in the different stages of tumorigenesis. They produce inflammatory cytokines to activate the adaptive immune system and are involved in the elimination of tumor cells. Macrophages’ release of mutation-inducing free radicals, such as nitrogen and oxygen intermediates as part of their cytotoxic/inflammatory response, contributes to tumor initiation. They also play important roles in tumor progression by secreting factors that promote angiogenesis, invasion, extracellular matrix remodeling and metastasis. However, while tumor development is modulated by macrophages, the tumor likewise can shape macrophage behavior, with the development of macrophages that exhibit immune suppressive traits, enabling tumor progression. This renders the immune system incapable of mounting an adequate response to tumor advancement. We have previously shown that peritoneal macrophages from mice with well-established mammary tumors are critically impaired in their immune functions. Here we examined whether defective macrophages from tumor hosts are already immune suppressed in their precursor stages as blood monocytes. Monocytes originate in the bone marrow and exit into the periphery where they circulate before entering tissues and differentiating into macrophages. Mononuclear cells were isolated from whole blood of D1-DMBA-3 mammary tumor-bearing and normal BALB/c mice and CD115+ monocytes were sorted from the mononuclear cell fraction. Our results show that CD115+ blood monocytes from mammary tumor-bearing mice exhibit an increase in numbers with a decrease in several key macrophage differentiation markers such as CD115, F4/80, CD68 and CD11b. Also, downregulation of MHC II, CD62L and the proangiogenic marker Tie2 is observed in these cells, whereas Gr1 and Ly6C are upregulated. Furthermore, gene microarray analysis of the expression of several inflammatory cytokines and chemokines indicates that resting and LPS-stimulated CD115+ sorted blood monocytes from tumor bearers display a majority of inflammatory genes, together with some anti-inflammatory genes as well; interestingly, CCR2 and CX3CR1 are both upregulated. Moreover, nitric oxide production is decreased and there is no production of arginase by these cells. Our results suggest that these monocytes do not share the phenotype or some of the suppressor features of myeloid-derived suppressor cells and express a mixture of inflammatory and anti-inflammatory properties. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3816.