Immunosuppressive myeloid cells under normal and neoplastic conditions

Although the importance of immunomodulatory myeloid cells in both normal physiology and carcinogenesis is well established, many questions remain regarding the specific roles and regulation of these cells. In this thesis, we explore the immunosuppressive features of macrophages [Mφs] and elucidate the mechanisms by which they suppress T cell proliferation/activation, the factors that regulate their suppressive properties, the relative potency of macrophage suppression compared to other myeloid cells, such as myeloid-derived suppressor cells (MDSCs), and the role these cells play in promoting tumor growth and metastasis. We demonstrate herein that in response to interferon (IFN)-beta, which is secreted by activated T cells, resident macrophages from non-tumor-bearing mice acquire immunosuppressive properties that are mediated by nitric oxide (NO). Moreover, our data reveal a novel role for Toll-like receptor (TLR)-induced IFN-beta in regulating the immunosuppressive properties of macrophages. We also demonstrate for the first time that in vitro culture conditions profoundly affect the immunosuppressive functions of MDSCs. Specifically, we show that serum antagonizes the suppressive abilities of MDSCs from 4T1 tumor-bearing mice and that the major serum protein albumin mediates these effects, in part by reducing reactive oxygen species (ROS) production from MDSCs. These findings have important implications, since the accurate detection and quantification of immunosuppression is critical for both the identification and functional analysis of tumor-induced MDSCs. We also explore the phenotypic and functional heterogeneity of tumor-induced myeloid cells and compare the immunosuppressive functions of different populations isolated from normal and tumor-bearing mice. We show that tumors that induce the accumulation of myeloid cells also enhance the suppressive functions of these cells. In addition, we demonstrate that, in vitro, tumor-induced macrophages are significantly more potent immune suppressors than tumor-induced MDSCs on a per cell basis, and suppress T cell responses via distinct mechanisms. Finally, we present data showing that treating metastatic mammary tumor-bearing mice with all-trans-retinoic acid (ATRA) decreases MDSCs, increases macrophages, and enhances metastatic growth. Taken together, these findings advance our understanding of the factors that regulate myeloid cell functions in normal and neoplastic tissues and may lead to improved immunotherapies to treat human disease.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat