Tumor-Derived Prostaglandin E2 Promotes p50 NF-κB-Dependent Differentiation of Monocytic MDSCs

Chiara Porta, Francesca Maria Consonni, Sara Morlacchi, Sabina Sangaletti, Augusto Bleve, Maria Grazia Totaro, Paola Larghi, Monica Rimoldi, Claudio Tripodo, Laura Strauss, Stefania Banfi, Mariangela Storto, Tiziana Pressiani, Lorenza Rimassa, Silvia Tartari, Alessandro Ippolito, Andrea Doni, Giulia Soldà, Stefano Duga, Viviana PiccoloRenato Ostuni, Gioacchino Natoli, Vincenzo Bronte, Fiorella Balzac, Emilia Turco, Emilio Hirsch, Mario P Colombo, Antonio Sica

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2874-2888
Number of pages15
JournalCancer Research
Volume80
Issue number13
DOIs
Publication statusPublished - Jul 1 2020

Keywords

  • Animals
  • Apoptosis
  • Cell Differentiation
  • Cell Proliferation
  • Colorectal Neoplasms/drug therapy
  • Dinoprostone/pharmacology
  • Humans
  • Immune Tolerance
  • Interferon-gamma/metabolism
  • Melanoma, Experimental/drug therapy
  • Mice
  • Monocytes/drug effects
  • Myeloid-Derived Suppressor Cells/drug effects
  • NF-kappa B p50 Subunit/genetics
  • Nitric Oxide/metabolism
  • Oxytocics/pharmacology
  • Pancreatic Neoplasms/drug therapy
  • Tumor Cells, Cultured

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