Tumor-derived prostaglandin E2 promotes p50 NF-κB-dependent differentiation of monocytic MDSC.

Myeloid-derived suppressor cells (MDSC) include immature monocytic (M-MDSC) and granulocytic (PMN-MDSC) cells that share the ability to suppress adaptive immunity and to hinder the effectiveness of anticancer treatments. Of note, in response to IFN gamma, M-MDSCs release the tumor-promoting and immunosuppressive molecule nitric oxide (NO), whereas macrophages largely express antitumor properties. Investigating these opposing activities, we found that tumor-derived prostaglandin E2 (PGE2) induces nuclear accumulation of p50 NF-kappa B in M-MDSCs, diverting their response to IFN gamma toward NO-mediated immunosuppression and reducing TNF alpha expression. At the genome level, p50 NF-kappa B promoted binding of STAT1 to regulatory regions of selected IFN gamma-dependent genes, including inducible nitric oxide synthase (Nos2). In agreement, ablation of p50 as well as pharmacologic inhibition of either the PGE2 receptor EP2 or NO production reprogrammed M-MDSCs toward a NOS2(low)/TNE alpha(high) phenotype, restoring the in vivo antitumor activity of IFNT. Our results indicate that inhibition of the PGE2/p50/NO axis prevents MDSC-suppressive functions and restores the efficacy of anticancer immunotherapy. Significance Tumor-derived PGE2-mediated induction of nuclear p50 NF-kappa B epigenetically reprograms the response of monocytic cells to IFN gamma toward an immunosuppressive phenotype, thus retrieving the anticancer properties of IFN gamma. [GRAPHICS] .