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

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 TNFa, 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 IFN? or the combination of TNFa 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 TNFa and the transcription factors NF-?B and STAT4 are major hubs regulating this process. These findings support the clinical evaluation of R848, IFN?, and/or TNFa plus IL-6 for intratumoral therapy of established cancers.

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