| First Author | Porta C | Year | 2020 |
| Journal | Cancer Res | Volume | 80 |
| Issue | 13 | Pages | 2874-2888 |
| PubMed ID | 32265223 | Mgi Jnum | J:290318 |
| Mgi Id | MGI:6437940 | Doi | 10.1158/0008-5472.CAN-19-2843 |
| Citation | Porta C, et al. (2020) Tumor-Derived Prostaglandin E2 Promotes p50 NF-kappaB-Dependent Differentiation of Monocytic MDSCs. Cancer Res 80(13):2874-2888 |
| abstractText | 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 IFNgamma, 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-kappaB in M-MDSCs, diverting their response to IFNgamma toward NO-mediated immunosuppression and reducing TNFalpha expression. At the genome level, p50 NF-kappaB promoted binding of STAT1 to regulatory regions of selected IFNgamma-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 NOS2(low)/TNFalpha(high) phenotype, restoring the in vivo antitumor activity of IFNgamma. 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-kappaB epigenetically reprograms the response of monocytic cells to IFNgamma toward an immunosuppressive phenotype, thus retrieving the anticancer properties of IFNgamma. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2874/F1.large.jpg. |
