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Front. Immunol. | doi: 10.3389/fimmu.2018.00608

Factors influencing the differentiation of human monocytic myeloid derived suppressor cells into inflammatory macrophages.

 Defne Bayik1, Debra Tross1 and  Dennis M. Klinman1*
  • 1Cancer and Inflammation Program, National Institutes of Health (NIH), United States

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.

Keywords: MDSC, inflammatory macrophage, Tumor Necrosis Factor-alpha, Interferon-gamma, STAT4, NF-kappa B

Received: 12 Jan 2018; Accepted: 12 Mar 2018.

Edited by:

Rudolf Lucas, Medical College of Georgia, Augusta University, United States

Reviewed by:

Nathan Karin, Technion – Israel Institute of Technology, Israel
Rachael Z. Murray, Queensland University of Technology, Australia
Christine E. Cutucache, University of Nebraska Omaha, United States  

Copyright: © 2018 Bayik, Tross and Klinman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Dennis M. Klinman, National Institutes of Health (NIH), Cancer and Inflammation Program, Bldg 567 Rm 205, NCI in Frederick, Bethesda, 20854, MD, United States,