Regulated expression of anti-apoptotic MCL-1 and A1 controls the population structure of myeloid derived suppressor cells (P1070)

Abstract

Abstract Myeloid-derived suppressor cells (MDSCs) are an immunosuppressive population of immature monocytic and granulocytic cells. MDSCs emerge from the bone marrow as inactive precursors and upon migration to sites of inflammation become activated regulatory cells. However, both the fate and key immunosuppressive subsets within the MDSC pool at inflammatory sites remain unclear. Here we show MDSCs express high amounts of anti-apoptotic MCL-1 and A1. We reasoned if MCL-1 was ablated in MDSC populations, MDSCs would be less suppressive and more prone to apoptotic death. However, MCL-1 deficient MDSCs were more suppressive than wild type (WT) MDSCs because MCL-1 deficient MDSCs were predominately monocytic in lineage. In the absence of MCL-1, granulocytic MDSCs are apoptotic and are not functional suppressor cells. These data define monocytic MDSCs as the key immunosuppressive population. When we sorted purified monocytic MDSCs from MCL-1 deficient mice we found they had reduced suppressive activity and higher apoptosis than sorted WT monocytic MDSCs. Further investigation demonstrated in the absence of MCL-1, regulated A1 expression in monocytic MDSCs is necessary for their full suppressive capacity and survival. Furthermore, we show GM-CSF is a key player in the survival of monocytic MDSCs via A1 regulation. These data have implications for the engineering of MDSCs as suppressors for autoimmune diseases and therapies to selectively ablate monocytic MDSCs in the treatment of cancer.