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Tumor-Derived Prostaglandin E2 Promotes p50 NF-κB-Dependent Differentiation of Monocytic MDSCs
Chiara Porta1,2, Francesca Maria Consonni3, Sara Morlacchi3
1Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy.
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 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. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2874/F1.large.jpg.
Insights
Tumor-derived prostaglandin E2 (PGE2) reprograms myeloid-derived suppressor cells (MDSCs) to suppress immunity. Inhibiting this PGE2/p50 NF-κB pathway restores the effectiveness of cancer immunotherapy by reprogramming MDSCs.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Myeloid-derived suppressor cells (MDSCs) suppress adaptive immunity and limit anticancer treatment efficacy.
- Monocytic MDSCs (M-MDSCs) release immunosuppressive nitric oxide (NO) upon IFNγ stimulation, unlike antitumor macrophages.
- Tumor-derived prostaglandin E2 (PGE2) influences M-MDSC function.
Purpose of the Study:
- To investigate how tumor-derived PGE2 affects M-MDSC responses to IFNγ.
- To identify molecular mechanisms underlying M-MDSC immunosuppressive functions.
- To explore strategies for restoring IFNγ's antitumor activity.
Main Methods:
- Analysis of p50 NF-κB nuclear accumulation in M-MDSCs.
- Genome-wide binding analysis of STAT1 in response to IFNγ.
- Pharmacologic inhibition of PGE2 receptor EP2 and NO production.
- Assessment of M-MDSC phenotype and in vivo antitumor activity.
Main Results:
- PGE2 induces p50 NF-κB nuclear accumulation in M-MDSCs, promoting NO release and reducing TNFα expression in response to IFNγ.
- p50 NF-κB facilitates STAT1 binding to regulatory regions of IFNγ-dependent genes, including Nos2.
- Inhibition of PGE2/EP2 or NO production reprogrammed M-MDSCs to a NOS2low/TNFαhigh phenotype.
- This reprogramming restored the in vivo antitumor activity of IFNγ.
Conclusions:
- Tumor-derived PGE2 epigenetically reprograms M-MDSCs via p50 NF-κB, shifting IFNγ response towards immunosuppression.
- Targeting the PGE2/p50/NO axis can overcome MDSC-mediated suppression.
- Inhibiting this axis restores IFNγ's anticancer properties and enhances immunotherapy efficacy.
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