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Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy

The tumor microenvironment (TME) is thought to influence the antitumor efficacy of immuno-oncology agents through various products of both tumor and stromal cells. One immune-suppressive factor is prostaglandin E(2) (PGE(2)), a lipid mediator whose biosynthesis is regulated by ubiquitously expressed...

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Autores principales: Nishibata, Toshihide, Amino, Nobuaki, Tanaka-Kado, Ruriko, Tsujimoto, Susumu, Kawashima, Tomoko, Konagai, Satoshi, Suzuki, Tomoyuki, Takeuchi, Masahiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10697779/
http://dx.doi.org/10.1155/2023/7133726
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author Nishibata, Toshihide
Amino, Nobuaki
Tanaka-Kado, Ruriko
Tsujimoto, Susumu
Kawashima, Tomoko
Konagai, Satoshi
Suzuki, Tomoyuki
Takeuchi, Masahiro
author_facet Nishibata, Toshihide
Amino, Nobuaki
Tanaka-Kado, Ruriko
Tsujimoto, Susumu
Kawashima, Tomoko
Konagai, Satoshi
Suzuki, Tomoyuki
Takeuchi, Masahiro
author_sort Nishibata, Toshihide
collection PubMed
description The tumor microenvironment (TME) is thought to influence the antitumor efficacy of immuno-oncology agents through various products of both tumor and stromal cells. One immune-suppressive factor is prostaglandin E(2) (PGE(2)), a lipid mediator whose biosynthesis is regulated by ubiquitously expressed cyclooxygenase- (COX-) 1 and inducible COX-2. By activating its receptors, PGE(2) induces immune suppression to modulate differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) rather than dendritic cells (DCs). Pharmacological blockade of prostaglandin E receptor 4 (EP4) causes a decrease in MDSCs, reprogramming of macrophage polarization, and increase in tumor-infiltrated T cells, leading to enhancement of antitumor immunity in preclinical models. Here, we report the effects of the highly potent EP4 antagonist ASP7657 on the DC population in tumor and antitumor immune activation in an immunocompetent mouse tumor model. Oral administration of ASP7657 inhibited tumor growth, which was accompanied by an increase in intratumor DC and CD8(+) T cell populations and a decrease in the M-MDSC population in a CT26 immunocompetent mouse model. The antitumor activity of ASP7657 was dependent on CD8(+) T cells and enhanced when combined with an antiprogrammed cell death-1 (PD-1) antibody. Notably, ASP7657 also significantly enhanced the antitumor efficacy of radiotherapy in an anti-PD-1 antibody refractory model. These results indicate that the therapeutic potential of ASP7657 arises via upregulation of DCs and subsequent CD8(+) T cell activation in addition to suppression of MDSCs in mouse models and that combining EP4 antagonists with radiotherapy or an anti-PD-1 antibody can improve antitumor efficacy.
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spelling pubmed-106977792023-12-06 Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy Nishibata, Toshihide Amino, Nobuaki Tanaka-Kado, Ruriko Tsujimoto, Susumu Kawashima, Tomoko Konagai, Satoshi Suzuki, Tomoyuki Takeuchi, Masahiro Biomed Res Int Research Article The tumor microenvironment (TME) is thought to influence the antitumor efficacy of immuno-oncology agents through various products of both tumor and stromal cells. One immune-suppressive factor is prostaglandin E(2) (PGE(2)), a lipid mediator whose biosynthesis is regulated by ubiquitously expressed cyclooxygenase- (COX-) 1 and inducible COX-2. By activating its receptors, PGE(2) induces immune suppression to modulate differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) rather than dendritic cells (DCs). Pharmacological blockade of prostaglandin E receptor 4 (EP4) causes a decrease in MDSCs, reprogramming of macrophage polarization, and increase in tumor-infiltrated T cells, leading to enhancement of antitumor immunity in preclinical models. Here, we report the effects of the highly potent EP4 antagonist ASP7657 on the DC population in tumor and antitumor immune activation in an immunocompetent mouse tumor model. Oral administration of ASP7657 inhibited tumor growth, which was accompanied by an increase in intratumor DC and CD8(+) T cell populations and a decrease in the M-MDSC population in a CT26 immunocompetent mouse model. The antitumor activity of ASP7657 was dependent on CD8(+) T cells and enhanced when combined with an antiprogrammed cell death-1 (PD-1) antibody. Notably, ASP7657 also significantly enhanced the antitumor efficacy of radiotherapy in an anti-PD-1 antibody refractory model. These results indicate that the therapeutic potential of ASP7657 arises via upregulation of DCs and subsequent CD8(+) T cell activation in addition to suppression of MDSCs in mouse models and that combining EP4 antagonists with radiotherapy or an anti-PD-1 antibody can improve antitumor efficacy. Hindawi 2023-11-28 /pmc/articles/PMC10697779/ http://dx.doi.org/10.1155/2023/7133726 Text en Copyright © 2023 Toshihide Nishibata et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Nishibata, Toshihide
Amino, Nobuaki
Tanaka-Kado, Ruriko
Tsujimoto, Susumu
Kawashima, Tomoko
Konagai, Satoshi
Suzuki, Tomoyuki
Takeuchi, Masahiro
Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy
title Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy
title_full Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy
title_fullStr Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy
title_full_unstemmed Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy
title_short Blockade of EP4 by ASP7657 Modulates Myeloid Cell Differentiation In Vivo and Enhances the Antitumor Effect of Radiotherapy
title_sort blockade of ep4 by asp7657 modulates myeloid cell differentiation in vivo and enhances the antitumor effect of radiotherapy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10697779/
http://dx.doi.org/10.1155/2023/7133726
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