Factors Influencing the Differentiation of Human Monocytic Myeloid-Derived Suppressor Cells Into Inflammatory Macrophages #MMPMID29632539
Bayik D; Tross D; Klinman DM
Front Immunol 2018[]; 9 (?): 608 PMID29632539show ga
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 (MAC(inflam)). This work demonstrates that TNFalpha, IL-6, and IL-10 produced by maturing mMDSC are critical to the generation of MAC(inflam). Neutralizing any one of these cytokines significantly inhibits R848-dependent mMDSC differentiation. mMDSC cultured in pro-inflammatory cytokine IFNgamma or the combination of TNFalpha plus IL-6 differentiate into MAC(inflam) 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 MAC(inflam) indicates that TNFalpha and the transcription factors NF-kappaB and STAT4 are major hubs regulating this process. These findings support the clinical evaluation of R848, IFNgamma, and/or TNFalpha plus IL-6 for intratumoral therapy of established cancers.
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Front+Immunol 2018 ; 9 (?): 608
