AUTHOR=Bayik Defne , Tross Debra , Klinman Dennis M. 

TITLE=Factors Influencing the Differentiation of Human Monocytic Myeloid-Derived Suppressor Cells Into Inflammatory Macrophages

JOURNAL=Frontiers in Immunology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00608

DOI=10.3389/fimmu.2018.00608

ISSN=1664-3224

ABSTRACT=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 TLR7/8 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 either cytokine significantly inhibits R848-dependent mMDSC differentiation.  mMDSC cultured in pro-inflammatory cytokine IFNγ or 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. RNAseq 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 intra-tumoral therapy of established cancers.