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

Chiara PORTA; FRANCESCA MARIA CONSONNI; Sara Morlacchi; Sabina Sangaletti; Augusto Bleve; Maria G. Totaro; Paola Larghi; Monica Rimoldi; Claudio Tripodo; Laura Strauss; Stefania Banfi; Mariangela Storto; Tiziana Pressiani; Lorenza Rimassa; Silvia Tartari; Alessandro Ippolito; Andrea Doni; Giulia Soldà; Stefano Duga; Viviana Piccolo; Renato Ostuni; Gioacchino Natoli; Vincenzo Bronte; Fiorella Balzac; Emilia Turco; Emilio Hirsch; Mario P. Colombo; Antonio SICA

doi:10.1158/0008-5472.CAN-19-2843

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

Chiara PORTA, FRANCESCA MARIA CONSONNI, Sara Morlacchi, Sabina Sangaletti, Augusto Bleve, Maria G. Totaro, Paola Larghi, Monica Rimoldi, Claudio Tripodo, Laura Strauss, Stefania Banfi, Mariangela Storto, Tiziana Pressiani, Lorenza Rimassa, Silvia Tartari, Alessandro Ippolito, Andrea Doni, Giulia Soldà, Stefano Duga, Viviana PiccoloRenato Ostuni, Gioacchino Natoli, Vincenzo Bronte, Fiorella Balzac, Emilia Turco, Emilio Hirsch, Mario P. Colombo, Antonio SICA

Dipartimento di Scienze del Farmaco

Risultato della ricerca: Contributo su rivista › Articolo in rivista › peer review

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.

Lingua originale	Inglese
Rivista	Cancer Research
DOI	https://doi.org/10.1158/0008-5472.CAN-19-2843
Stato di pubblicazione	Pubblicato - 2020

Keywords

Myeloid-derived suppressor cells
NF-κB
immunosuppression
immunotherapy
interferon-γ
prostaglandin E2
tumor microenvironment

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10.1158/0008-5472.CAN-19-2843

https://hdl.handle.net/11579/113043

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PORTA, C., CONSONNI, FRANCESCA. MARIA., Morlacchi, S., Sangaletti, S., Bleve, A., Totaro, M. G., Larghi, P., Rimoldi, M., Tripodo, C., Strauss, L., Banfi, S., Storto, M., Pressiani, T., Rimassa, L., Tartari, S., Ippolito, A., Doni, A., Soldà, G., Duga, S., ... SICA, A. (2020). Tumor-derived prostaglandin E2 promotes p50 NF-κB-dependent differentiation of monocytic MDSC. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-19-2843

@article{57396d82e3e64d3e98e0c271a0351bb9,

title = "Tumor-derived prostaglandin E2 promotes p50 NF-κB-dependent differentiation of monocytic MDSC.",

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.",

keywords = "Myeloid-derived suppressor cells, NF-κB, immunosuppression, immunotherapy, interferon-γ, prostaglandin E2, tumor microenvironment, Myeloid-derived suppressor cells, NF-κB, immunosuppression, immunotherapy, interferon-γ, prostaglandin E2, tumor microenvironment",

author = "Chiara PORTA and CONSONNI, {FRANCESCA MARIA} and Sara Morlacchi and Sabina Sangaletti and Augusto Bleve and Totaro, {Maria G.} and Paola Larghi and Monica Rimoldi and Claudio Tripodo and Laura Strauss and Stefania Banfi and Mariangela Storto and Tiziana Pressiani and Lorenza Rimassa and Silvia Tartari and Alessandro Ippolito and Andrea Doni and Giulia Sold{\`a} and Stefano Duga and Viviana Piccolo and Renato Ostuni and Gioacchino Natoli and Vincenzo Bronte and Fiorella Balzac and Emilia Turco and Emilio Hirsch and Colombo, {Mario P.} and Antonio SICA",

note = "Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",

year = "2020",

doi = "10.1158/0008-5472.CAN-19-2843",

language = "English",

journal = "Cancer Research",

issn = "1538-7445",

publisher = "American Association for Cancer Research Inc.",

}

PORTA, C , CONSONNI, FRANCESCAMARIA, Morlacchi, S, Sangaletti, S, Bleve, A, Totaro, MG, Larghi, P, Rimoldi, M, Tripodo, C, Strauss, L, Banfi, S, Storto, M, Pressiani, T, Rimassa, L, Tartari, S, Ippolito, A, Doni, A, Soldà, G, Duga, S, Piccolo, V, Ostuni, R, Natoli, G, Bronte, V, Balzac, F, Turco, E, Hirsch, E, Colombo, MP & SICA, A 2020, 'Tumor-derived prostaglandin E2 promotes p50 NF-κB-dependent differentiation of monocytic MDSC.', Cancer Research. https://doi.org/10.1158/0008-5472.CAN-19-2843

TY - JOUR

T1 - Tumor-derived prostaglandin E2 promotes p50 NF-κB-dependent differentiation of monocytic MDSC.

AU - PORTA, Chiara

AU - CONSONNI, FRANCESCA MARIA

AU - Morlacchi, Sara

AU - Sangaletti, Sabina

AU - Bleve, Augusto

AU - Totaro, Maria G.

AU - Larghi, Paola

AU - Rimoldi, Monica

AU - Tripodo, Claudio

AU - Strauss, Laura

AU - Banfi, Stefania

AU - Storto, Mariangela

AU - Pressiani, Tiziana

AU - Rimassa, Lorenza

AU - Tartari, Silvia

AU - Ippolito, Alessandro

AU - Doni, Andrea

AU - Soldà, Giulia

AU - Duga, Stefano

AU - Piccolo, Viviana

AU - Ostuni, Renato

AU - Natoli, Gioacchino

AU - Bronte, Vincenzo

AU - Balzac, Fiorella

AU - Turco, Emilia

AU - Hirsch, Emilio

AU - Colombo, Mario P.

AU - SICA, Antonio

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Myeloid-derived suppressor cells

KW - NF-κB

KW - immunosuppression

KW - immunotherapy

KW - interferon-γ

KW - prostaglandin E2

KW - tumor microenvironment

KW - Myeloid-derived suppressor cells

KW - NF-κB

KW - immunosuppression

KW - immunotherapy

KW - interferon-γ

KW - prostaglandin E2

KW - tumor microenvironment

UR - https://iris.uniupo.it/handle/11579/113043

U2 - 10.1158/0008-5472.CAN-19-2843

DO - 10.1158/0008-5472.CAN-19-2843

M3 - Article

SN - 1538-7445

JO - Cancer Research

JF - Cancer Research

ER -

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

Abstract

Keywords

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