Abstract 2876: Inflammation of the tumor microenvironment is regulated by myeloid derived suppressor cell and macrophage crosstalk.
Authors: Beury Daniel W. , Parker Katherine H. , Ostrand-Rosenberg Suzanne 
Published: August 2014

Abstract
Myeloid-Derived Suppressor Cells (MDSC) polarize macrophages to a Type II tumor-promoting phenotype via MDSC-macrophage crosstalk. We previously demonstrated that MDSC produce IL-10 which inhibits macrophage production of IL-12, and MDSC production of IL-10 is dependent on TLR4 and enhanced by cell-cell contact with macrophages. However, the role of inflammation in MDSC-macrophage crosstalk is not well defined. To determine the role of inflammation, we utilized wild type, IL-6-/-, and IL-10-/- mice bearing syngeneic 4T1 mammary carcinoma. IL-10 is classically an anti-inflammatory cytokine. In contrast, IL-6 is a pro-inflammatory cytokine that is secreted by activated Type 1 macrophages, is found at higher levels in tumor-bearing patients, and is an inducer of MDSC. 4T1-induced MDSC and macrophages express both IL-6 and IL-10 receptors, suggesting that they have the potential to respond to both cytokines. To determine if IL-6 and IL-10 contribute to tumor progression by modulating MDSC-macrophage crosstalk, MDSC from wild type or IL-10-/- mice bearing 4T1 tumors were cultured with macrophages from wild type or IL-6-/- BALB/c mice. Although MDSC are typically pro-inflammatory cells, they significantly decreased macrophage production of IL-6, suggesting that MDSC can also function as anti-inflammatory cells. IL-6 levels are important in vivo since primary 4T1 tumors grow more slowly in IL-6-deficient mice, and these mice have significantly extended survival compared to wild type BALB/c mice. Anti-inflammatory effects are further exacerbated by macrophages themselves, since their production of IL-6 increases MDSC production of IL-10. However, macrophage-produced IL-6 affects MDSC indirectly, as incubation of MDSC with exogenous IL-6 in the absence of macrophages does not increase IL-10 production. Although IL-10 is classically considered as an anti-inflammatory cytokine, it contributes to tumor progression because 4T1-bearing IL-10-/- mice have delayed primary tumor progression and extended survival vs. wild type mice. These data demonstrate that MDSC have both pro-inflammatory and anti-inflammatory effects and that MDSC-macrophage cross-talk contributes to the overall milieu of IL-10 and IL-6 within the tumor microenvironment. Since IL-6 is a signature cytokine of anti-tumor M1-like macrophages, these data also suggest that although MDSC may decrease inflammation through their production of IL-10, this effect neither promotes the development of tumoricidal macrophages nor decreases tumor progression.
Supported by NIH R01 CA115880, RO1CA84232, and DOD BCRP W81XWH-11-1-0115
Citation Format: Daniel W. Beury, Katherine H. Parker, Suzanne Ostrand-Rosenberg. Inflammation of the tumor microenvironment is regulated by myeloid derived suppressor cell and macrophage crosstalk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2876. doi:10.1158/1538-7445.AM2013-2876