NIH Research Festival
Monocytic myeloid-derived suppressor cells (mMDSC) have immunosuppressive properties. Their activity helps the host avoid autoimmune disease but when mMDSC accumulate in a tumor bed, they prevent NK and T cells from eliminating the cancer. We previously found that R848 (a TLR7/8 agonist) reverses this immunosuppression by inducing mMDSC to differentiate into tumoricidal M1 macrophages. To identify the mechanism underlying this effect, we neutralized various cytokines/chemokines in R848 stimulated mMDSC cultures. Blocking IL-6, IL-10, IL-12 and/or TNFα inhibited R848-mediated generation of M1 macrophages. Moreover, combinations of these cytokines induced mMDSC to differentiation more effectively than R848, generating M1 macrophages that efficiently lysed tumor targets. Microarray analysis of the regulatory networks activated following treatment of mMDSC with cytokine combinations or R848 showed that M1 differentiation universally proceeded through a conserved NF-κB, STAT1 and IRF7-dependent pathway. These findings can be harnessed in cancer therapy to induce suppresssive mMDSC to differentiate into tumoricidal M1 macrophages.
Scientific Focus Area: Immunology
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