| Autor: |
Antonio Sica, Mario P. Colombo, Emilio Hirsch, Emilia Turco, Fiorella Balzac, Vincenzo Bronte, Gioacchino Natoli, Renato Ostuni, Viviana Piccolo, Stefano Duga, Giulia Soldà, Andrea Doni, Alessandro Ippolito, Silvia Tartari, Lorenza Rimassa, Tiziana Pressiani, Mariangela Storto, Stefania Banfi, Laura Strauss, Claudio Tripodo, Monica Rimoldi, Paola Larghi, Maria Grazia Totaro, Augusto Bleve, Sabina Sangaletti, Sara Morlacchi, Francesca Maria Consonni, Chiara Porta |
| Rok vydání: |
2023 |
| DOI: |
10.1158/0008-5472.c.6511398.v1 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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