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EnglishMyeloid-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.
| Data di pubblicazione: | 2020 |
| Titolo: | Tumor-derived prostaglandin E2 promotes p50 NF-κB-dependent differentiation of monocytic MDSC |
| Autori: | |
| Citazione: | 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. |
| Rivista: | |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1158/0008-5472.CAN-19-2843 |
| 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 Scientifico Disciplinare: | Settore MED/08 - Anatomia Patologica |
| Appare nelle tipologie: | 1.01 Articolo in rivista |
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