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

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

Risultato della ricerca: Articlepeer review

19 Citazioni (Scopus)

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 hinder the effectiveness of anti-cancer treatments. Of note, in response to interferon-γ (IFNγ) M-MDSC release the tumor-promoting and immunosuppressive molecule nitric oxide (NO), whereas macrophages largely express anti-tumor properties. Investigating these opposing activities, we found that tumor-derived prostaglandin E2 (PGE2) induces nuclear accumulation of p50 NF-κB in M-MDSC, diverting their response to IFNγ towards 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 pharmacological inhibition of either the PGE2 receptor EP2 or NO production reprogrammed M-MDSC towards 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.
Lingua originaleEnglish
pagine (da-a)canres.2843.2019-
Numero di pagine0
RivistaCancer Research
Stato di pubblicazionePublished - 2020

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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