Tumor development is associated with changes in hematopoiesis that lead to an increase in myelomonocytic cells in systemic sites as well as within the tumor tissue. The accumulation of myeloid cells within tumors not only promotes angiogenesis and tissue remodeling required for tumor growth but also maintains the tumor milieu as an immunosuppressive environment. We have previously shown that attenuated strains of the facultative anaerobic bacteria, Salmonella enterica serovar Typhimrium, can effectively retard tumor growth in a therapeutic melanoma model. Given that Salmonella organisms utilize host macrophages as their primary niche for survival, we investigated the consequences of Salmonella treatment on myeloid cell recruitment, phenotypic characteristics and functional activation within tumor tissue of B16.F1 melanoma-bearing animals. Treatment with Salmonella led a preferential expansion, within spleen and tumor tissues, of CD11b+Gr-1+, but not CD11b+Gr-1-, myeloid cells. Using 6-color FACS analysis, CD11b+Gr-1+ cells were shown to exhibit significant up-regulation in the expression of activation markers, including MHC class II, CD80, and Sca-1/Ly6A proteins. Moreover, the functional activities of total tumor infiltrating cells or CD11b-purified cells from tumor tissue were assessed by qRT-PCR. Salmonella treatment induced a dramatic increase in iNOS and IFN-g gene expression but inhibited ARG1 and IL-4 genes. Further, while expression of TGF-b and VEGF was reduced, the level of inflammation-related S100A9 gene was increased. Our findings demonstrate that systemic administration of attenuated Salmonella leads to phenotypic and functional changes in tumor myeloid suppressor cells, with a shift from a predominantly M2 phenotype to an activated, effector macrophage phenotype.

Citation Format: Basel K. Al-Ramadi, Suneesh Kaimala, Yassir A. Mohamed, Jincy M. Issac, Eyad Elkord, Salem Chouaib, Maria J. Fernandez-Cabezudo. Targeting of tumor myeloid suppressor cells by Salmonella bacteria causes a shift to M1 phenotype and leads to inhibition of tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3632. doi:10.1158/1538-7445.AM2014-3632