MIF is necessary for late-stage melanoma patient MDSC immune suppression and differentiation

Abstract Patients diagnosed with unresectable stage IV melanoma have an average survival of 6–10 months; a survival time that hasn’t changed significantly in the last 30 years. Despite some encouraging improvements in response rates and overall survival in patients receiving Ipilimumab (anti-CTLA-4) and/or Nivolumab (anti-PD-1) immunotherapies, the majority of patients will ultimately progress. Myeloid-derived suppressor cells (MDSCs) are potently immunosuppressive innate immune cells that accumulate in advanced cancer patients and actively inhibit anti-tumor T lymphocyte responses; therefore, can contribute to immunotherapeutic resistance. Increased circulating MDSCs in stage III/IV melanoma patients predict patient mortality and directly correlate with reduced melanoma antigen-specific T cells. Our results demonstrate that circulating monocytic MDSCs are found in significantly higher numbers in chemotherapy naïve late stage melanoma patients and the immunosuppressive activity of these cells is highly reliant upon the innate immunomodulatory cytokine, macrophage migration inhibitory factor (MIF). 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 melanoma MDSC induction and immune suppressive function and that therapeutic targeting of MIF may provide a novel means of inducing anti-tumor immune responses in late stage melanoma patients.