Carcinomasby Metastatic Murine Mammary Myeloid-Derived Suppressor Cells Induced Suppressors Ex Vivo Than Immature Macrophages Are More Potent Immune

Myeloid-derived suppressor cells (MDSCs) are emerging as potential promoters of metastatic tumor growth, and there is interest in targeting immature MDSCs by inducing their differentiation into more mature myeloid cells. We used all-trans retinoic acid (ATRA) to differentiate MDSCs in mice bearing metastatic 4T1 or 4TO7 murine mammary tumors, and assessed the immune-suppressive mechanisms and potencies of different myeloid cell subpopulations. Metastatic mammary tumors induced the accumulation of distinct populations of immature CD11b + Gr1 + F4/80 2 Ly6C mid Ly6G + MDSCs (“Gr1 + cells”) and mature CD11b + Gr1 2 F4/80 + cells (“F4/80 + cells”) in metastatic target organs. ATRA triggered the differentiation of Gr1 + cells into F4/80 + cells in the lungs and, unexpectedly, enhanced pulmonary metastatic tumor growth. We found that F4/80 + Ly6C 2 Ly6G 2 mature macrophages (M f s) were up to 30-fold more potent immune suppressors than Gr1 + cells on a per-cell basis, which we postulate may contribute to the increased metastatic growth observed with ATRA treatment. F4/80 + cells and Gr1 + cells used different reactive oxygen species (ROS)–mediated mechanisms of immunosuppression ex vivo, with F4/80 + cells producing higher levels of ROS, which is consistent with their superior immunosuppressive abilities. These data highlight the potent immunosuppressive functions of M f s, reveal that M f s can suppress T cell responses via ROS production, and suggest that ROS inhibitors may be useful in promoting antitumor immune