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.

Porta, C., Consonni, F.M., Morlacchi, S., Sangaletti, S., Bleve, A., Totaro, M.G., et al. (2020). Tumor-derived prostaglandin E2 promotes p50 NF-κB-dependent differentiation of monocytic MDSC. CANCER RESEARCH, canres.2843.2019 [10.1158/0008-5472.CAN-19-2843].

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

Tripodo, Claudio;
2020

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.
Settore MED/08 - Anatomia Patologica
Porta, C., Consonni, F.M., Morlacchi, S., Sangaletti, S., Bleve, A., Totaro, M.G., et al. (2020). Tumor-derived prostaglandin E2 promotes p50 NF-κB-dependent differentiation of monocytic MDSC. CANCER RESEARCH, canres.2843.2019 [10.1158/0008-5472.CAN-19-2843].
File in questo prodotto:
File Dimensione Formato  
Porta et all_.pdf

Solo gestori archvio

Tipologia: Versione Editoriale
Dimensione 1.3 MB
Formato Adobe PDF
1.3 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10447/416471
Citazioni
  • ???jsp.display-item.citation.pmc??? 35
  • Scopus 42
  • ???jsp.display-item.citation.isi??? 42
social impact