Highly aggressive cancers "entrain" innate and adaptive immune cells to suppress anti-tumor lymphocyte responses. Circulating myeloid-derived suppressor cells (MDSCs) constitute the bulk of monocytic immunosuppressive activity in late stage melanoma patients. Previous studies revealed that monocyte-derived macrophage migration inhibitory factor (MIF) is necessary for the immune suppressive function of tumor-associated macrophages (TAMs) and MDSCs in mouse models of melanoma. In the current study we sought to determine whether MIF contributes to human melanoma MDSC induction and T-cell immunosuppression using melanoma patient-derived MDSCs and an ex vivo co-culture model of human melanoma-induced MDSC. We now report that circulating MDSCs isolated from late stage melanoma patients are reliant upon MIF for suppression of antigen-independent T-cell activation and that MIF is necessary for maximal reactive oxygen species (ROS) generation in these cells. Moreover, inhibition of MIF results in a functional reversion from immune suppressive MDSC to an immunostimulatory dendritic cell (DC)-like phenotype that is at least partly due to reductions in MDSC prostaglandin E2 (PGE2). These findings indicate that monocyte-derived MIF is centrally involved in human monocytic MDSC induction/immune suppressive function and that therapeutic targeting of MIF may provide a novel means of inducing anti-tumor DC responses in late stage melanoma patients.
- Received March 12, 2015.
- Revision received September 22, 2015.
- Accepted October 16, 2015.
- Copyright © 2015, American Association for Cancer Research.