Tumor-derived prostaglandin E2 promotes p50 NF-kB-dependent differentiation of monocytic MDSCs: Cancer Research

C. Porta, F.M. Consonni, S. Morlacchi, S. Sangaletti, A. Bleve, M.G. Totaro, P. Larghi, M. Rimoldi, C. Tripodo, L. Strauss, S. Banfi, M. Storto, T. Pressiani, L. Rimassa, S. Tartari, A. Ippolito, A. Doni, G. Solda, S. Duga, V. PiccoloR. Ostuni, G. Natoli, V. Bronte, F. Balzac, E. Turco, E. Hirsch, M.P. Colombo, A. 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 IFNg, 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-kB in M-MDSCs, diverting their response to IFNg toward NO-mediated immunosuppression and reducing TNFa expression. At the genome level, p50 NF-kB promoted binding of STAT1 to regulatory regions of selected IFNg-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/TNFahigh phenotype, restoring the in vivo antitumor activity of IFNg. Our results indicate that inhibition of the PGE2/p50/NO axis prevents MDSC-suppressive functions and restores the efficacy of anticancer immunotherapy. © 2020 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)2874-2888
Number of pages15
JournalCancer Res.
Volume80
Issue number13
DOIs
Publication statusPublished - 2020

Keywords

  • gamma interferon
  • immunoglobulin enhancer binding protein
  • inducible nitric oxide synthase
  • nitric oxide
  • prostaglandin E receptor 2
  • prostaglandin E2
  • STAT1 protein
  • tumor necrosis factor
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • antineoplastic activity
  • Article
  • cancer immunotherapy
  • cell differentiation
  • cell nucleus
  • cellular distribution
  • controlled study
  • human
  • human cell
  • immune response
  • immunomodulation
  • macrophage
  • monocytic myeloid-derived suppressor cell
  • mouse
  • myeloid-derived suppressor cell
  • nonhuman
  • priority journal
  • protein binding
  • protein expression
  • tumor immunity

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