Tumor Microenvironment Induces Profound Immune Suppression: Macrophages From Peripheral And Tumor Locations Differ In Their Degrees Of Inflammatory Impairment

Macrophages are key players in the inflammatory response and exhibit significant roles in the different stages of tumor progression. We have previously reported the deficient functions of elicited macrophages recruited to the peritoneal cavity of mice bearing advanced D1-DMBA3 mammary tumors (T-PEMs). We showed that these 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 and proinflammatory signaling pathways intermediates and are less differentiated. Moreover, due in part to NFκB downregulation, increased apoptosis is observed in T-PEMs, a phenomenon which we reported for the first time that may contribute to increased myelopoiesis in tumor hosts. We have also recently examined the characteristics of blood monocytes from mice bearing the same mammary tumors and have 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 animal 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, yet upregulate IL-12p40, IL-23 and IL-10. 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. Interestingly, macrophages from tumor-bearing mice block T-cell proliferation, with TAMs exerting a more powerful inhibitory effect than T-PEMs. Also, TAMs are more prone to apoptosis than T-PEMs due to a higher expression of activated caspase 3 and downregulation of Bclx. TAMs also exhibit lower levels of differentiation than T-PEMs. In addition, our results show that T-PEMs and TAMs have equally impaired phagocytic capacity compared with fully-phagocytic N-PEMs. Moreover, TAMs constitutively express iNOS and produce nitric oxide as compared with T-PEMs, and they have constitutively lower arginase activity than T-PEMs. Furthermore, TAMs are Gr-1 high and CD11b low , thus they are not classic myeloid-derived suppressor cells. Our results show that different locations in tumor hosts determine macrophage phenotypes and functions. The tumor microenvironment, as the location in most intimate contact with tumor cells, is the one that most alters macrophage activity. This is not only due to the occurrence of higher levels of tumor factors secreted by tumor cells, but also to the presence of other cell types that may interact with macrophages and modulate their activity. Targeting these tumor factors and cells in the tumor microenvironment will allow reversion of macrophage dysfunction. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 449. doi:10.1158/1538-7445.AM2011-449