Tumor-Derived Prostaglandin E2 Promotes p50 NF-κB-Dependent Differentiation of Monocytic MDSCs.
Chiara PortaFrancesca Maria ConsonniSara MorlacchiSabina SangalettiAugusto BleveMaria Grazia TotaroPaola LarghiMonica RimoldiClaudio TripodoLaura StraussStefania BanfiMariangela StortoTiziana PressianiLorenza RimassaSilvia TartariAlessandro IppolitoAndrea DoniGiulia SoldàStefano DugaViviana PiccoloRenato OstuniGioacchino NatoliVincenzo BronteFiorella BalzacEmilia TurcoEmilio HirschMario Paolo ColomboAntonio SicaPublished in: Cancer research (2020)
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 IFNγ, 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-κB in M-MDSCs, diverting their response to IFNγ toward NO-mediated immunosuppression and reducing TNFα expression. At the genome level, p50 NF-κB promoted binding of STAT1 to regulatory regions of selected IFNγ-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 NOS2low/TNFαhigh phenotype, restoring the in vivo antitumor activity of IFNγ. 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-κB epigenetically reprograms the response of monocytic cells to IFNγ toward an immunosuppressive phenotype, thus retrieving the anticancer properties of IFNγ. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2874/F1.large.jpg.
Keyphrases
- nitric oxide synthase
- induced apoptosis
- nitric oxide
- signaling pathway
- dendritic cells
- immune response
- cell cycle arrest
- pi k akt
- oxidative stress
- lps induced
- randomized controlled trial
- rheumatoid arthritis
- nuclear factor
- poor prognosis
- genome wide
- endoplasmic reticulum stress
- cell death
- gene expression
- binding protein
- mouse model
- catheter ablation