@article{8c94edc2286d46db918d8b14d0a5dbf1,
title = "Tumor-derived prostaglandin E2 promotes p50 NF-kB-dependent differentiation of monocytic MDSCs: Cancer Research",
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 IFNg, 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-kB in M-MDSCs, diverting their response to IFNg toward NO-mediated immunosuppression and reducing TNFa expression. At the genome level, p50 NF-kB promoted binding of STAT1 to regulatory regions of selected IFNg-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/TNFahigh phenotype, restoring the in vivo antitumor activity of IFNg. Our results indicate that inhibition of the PGE2/p50/NO axis prevents MDSC-suppressive functions and restores the efficacy of anticancer immunotherapy. {\textcopyright} 2020 American Association for Cancer Research.",
keywords = "gamma interferon, immunoglobulin enhancer binding protein, inducible nitric oxide synthase, nitric oxide, prostaglandin E receptor 2, prostaglandin E2, STAT1 protein, tumor necrosis factor, animal cell, animal experiment, animal model, animal tissue, antineoplastic activity, Article, cancer immunotherapy, cell differentiation, cell nucleus, cellular distribution, controlled study, human, human cell, immune response, immunomodulation, macrophage, monocytic myeloid-derived suppressor cell, mouse, myeloid-derived suppressor cell, nonhuman, priority journal, protein binding, protein expression, tumor immunity",
author = "C. Porta and F.M. Consonni and S. Morlacchi and S. Sangaletti and A. Bleve and M.G. Totaro and P. Larghi and M. Rimoldi and C. Tripodo and L. Strauss and S. Banfi and M. Storto and T. Pressiani and L. Rimassa and S. Tartari and A. Ippolito and A. Doni and G. Solda and S. Duga and V. Piccolo and R. Ostuni and G. Natoli and V. Bronte and F. Balzac and E. Turco and E. Hirsch and M.P. Colombo and A. Sica",
note = "Cited By :14 Export Date: 11 March 2021 CODEN: CNREA Correspondence Address: Sica, A.; Universita del Piemonte Orientale “Amedeo Avogadro, Italy; email: antonio.sica@uniupo.it Chemicals/CAS: gamma interferon, 82115-62-6; inducible nitric oxide synthase, 501433-35-8; nitric oxide, 10102-43-9; prostaglandin E2, 363-24-6 Funding details: European Research Council, ERC, ERCAdGN.692789 Funding details: Fondazione Cariplo, 2016/0871 Funding details: Ministero della Salute, GR-2013-02355637, RF-2016-0236842 Funding details: Ministero dell{\textquoteright}Istruzione, dell{\textquoteright}Universit{\`a} e della Ricerca, MIUR, 2017BA9LM5_001 Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC, 10137, 12162, 12810, 15585, 19682, 19885, 22757 Funding details: Universit{\`a} degli Studi del Piemonte Orientale, UPO Funding text 1: This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) Italy (12810, to S. Sangaletti; IG numbers 10137 to M.P. Colombo; IG numbers 15585, 19885 to A. Sica; AIRC 5 per Mille, number 22757 to A. Sica; AIRC 5 per Mille, Program Innovative Tools for Cancer Risk Assessment and Diagnosis, number 12162 to C. Tripodo; Three-Year fellowship ?Pierluigi Meneghelli,? project code 19682, to F.M. Consonni). Ministero dell'istruzione, dell'Universita e della Ricerca (MIUR), Italy (PRIN 2015YYKPNN and 2017BA9LM5_001 to A. Sica); Ministero della Salute, Ricerca Finalizzata RF-2016-0236842 to A. Sica and GR-2013-02355637 to S. Sangaletti; European Research Council (ERC) Advanced grant ERCAdGN.692789 to G. Natoli; Fondazione Cariplo 2016/0871 to A. Sica, Associazione ?Augusto per la Vita,? Novellara, Italy, to A. Sica, Associazione ?Medicine Rocks,? Milan, Italy, to A. Sica, and Universita del Piemonte Orientale, Novara, Italy, Ricerca locale 2019 to C. Porta. Funding text 2: This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) Italy (12810, to S. Sangaletti; IG numbers 10137 to M.P. Colombo; IG numbers 15585, 19885 to A. Sica; AIRC 5 per Mille, number 22757 to A. Sica; AIRC 5 per Mille, Program Innovative Tools for Cancer Risk Assessment and Diagnosis, number 12162 to C. Tripodo; Three-Year fellowship “Pierluigi Meneghelli,” project code 19682, to F.M. Consonni). Ministero dell'istruzione, dell'Universit{\`a}e della Ricerca (MIUR), Italy (PRIN 2015YYKPNN and 2017BA9LM5_001 to A. Sica); Ministero della Salute, Ricerca Finalizzata RF-2016-0236842 to A. Sica and GR-2013-02355637 to S. Sangaletti; European Research Council (ERC) Advanced grant ERCAdGN.692789 to G. Natoli; Fondazione Cariplo 2016/0871 to A. Sica, Associa-zione “Augusto per la Vita,” Novellara, Italy, to A. Sica, Associazione “Medicine Rocks,” Milan, Italy, to A. Sica, and Universit{\`a}del Piemonte Orientale, Novara, Italy, Ricerca locale 2019 to C. Porta.",
year = "2020",
doi = "10.1158/0008-5472.CAN-19-2843",
language = "English",
volume = "80",
pages = "2874--2888",
journal = "Cancer Res.",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "13",
}