%A Bayik,Defne %A Tross,Debra %A Klinman,Dennis M. %D 2018 %J Frontiers in Immunology %C %F %G English %K MDSC,inflammatory macrophage,Tumor Necrosis Factor-alpha,Interferon-gamma,STAT4,NF-kappa B %Q %R 10.3389/fimmu.2018.00608 %W %L %M %P %7 %8 2018-March-26 %9 Original Research %# %! Differentiation of human mMDSC into inflammatory macrophages %* %< %T Factors Influencing the Differentiation of Human Monocytic Myeloid-Derived Suppressor Cells Into Inflammatory Macrophages %U https://www.frontiersin.org/articles/10.3389/fimmu.2018.00608 %V 9 %0 JOURNAL ARTICLE %@ 1664-3224 %X Monocytic myeloid-derived suppressor cells (mMDSC) accumulate within tumors where they create an immunosuppressive milieu that inhibits the activity of cytotoxic T and NK cells thereby allowing cancers to evade immune elimination. The toll-like receptors 7/8 agonist R848 induces human mMDSC to mature into inflammatory macrophage (MACinflam). This work demonstrates that TNFα, IL-6, and IL-10 produced by maturing mMDSC are critical to the generation of MACinflam. Neutralizing any one of these cytokines significantly inhibits R848-dependent mMDSC differentiation. mMDSC cultured in pro-inflammatory cytokine IFNγ or the combination of TNFα plus IL-6 differentiate into MACinflam more efficiently than those treated with R848. These mMDSC-derived macrophages exert anti-tumor activity by killing cancer cells. RNA-Seq analysis of the genes expressed when mMDSC differentiate into MACinflam indicates that TNFα and the transcription factors NF-κB and STAT4 are major hubs regulating this process. These findings support the clinical evaluation of R848, IFNγ, and/or TNFα plus IL-6 for intratumoral therapy of established cancers.