PGE2-EP2/EP4 signaling elicits immunosuppression by driving the mregDC-Treg axis in inflammatory tumor microenvironment

Thumkeo, Dean; Punyawatthananukool, Siwakorn; Prasongtanakij, Somsak; Matsuura, Ryuma; Arima, Kentaro; Nie, Huan; Yamamoto, Rie; Aoyama, Naohiro; Hamaguchi, Hisao; Sugahara, Shingo; Takeda, Shinobu; Charoensawan, Varodom; Tanaka, Atsushi; Sakaguchi, Shimon; Narumiya, Shuh

doi:10.1016/j.celrep.2022.110914

Cited by 62 publications

(58 citation statements)

References 51 publications

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“…First, by impairing NK viability and chemokine production, and secondly by causing downregulation of chemokine receptor expression in cDC1 ( 79 ). Also, PGE2-EP2/EP4 signaling promotes inflammation by inducing expression of the NF-κB genes in myeloid cells and elicits immunosuppression by driving the mregDC-Treg axis for Treg recruitment and activation in the tumor ( 80 ).…”

Section: Modulation Of DC Function In the Tumor Microenvironmentmentioning

confidence: 99%

Strategies to overcome DC dysregulation in the tumor microenvironment

2022

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Dendritic cells (DCs) play a key role to modulate anti-cancer immunity in the tumor microenvironment (TME). They link innate to adaptive immunity by processing and presenting tumor antigens to T cells thereby initiating an anti-tumor response. However, subsets of DCs also induce immune-tolerance, leading to tumor immune escape. In this regard, the TME plays a major role in adversely affecting DC function. Better understanding of DC impairment mechanisms in the TME will lead to more efficient DC-targeting immunotherapy. Here, we review the different subtypes and functions of DCs in the TME, including conventional DCs, plasmacytoid DC and the newly proposed subset, mregDC. We further focus on how cancer cells modulate DCs to escape from the host’s immune-surveillance. Immune checkpoint expression, small molecule mediators, metabolites, deprivation of pro-immunogenic and release of pro-tumorigenic cytokine secretion by tumors and tumor-attracted immuno-suppressive cells inhibit DC differentiation and function. Finally, we discuss the impact of established therapies on DCs, such as immune checkpoint blockade. Creative DC-targeted therapeutic strategies will be highlighted, including cancer vaccines and cell-based therapies.

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Section: Modulation Of DC Function In the Tumor Microenvironmentmentioning

confidence: 99%

Strategies to overcome DC dysregulation in the tumor microenvironment

2022

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“…On the inflammatory side, PGE2-matured moDCs show a concentration-dependent increase in co-stimulatory marker expression (CD86, CD83, and HLA-DR), higher T cell proliferation, and upregulation of CCR7 expression which enhances the migration of moDCs [ 6 , 14 , 15 , 18 ]. Nevertheless, PGE2 also promotes local and systemic DC dysfunction in cancer [ 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Tailored PGE2 Immunomodulation of moDCs by Nano-Encapsulated EP2/EP4 Antagonists

Bödder

Kok

Fauerbach

et al. 2023

IJMS

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Prostaglandin E2 (PGE2) is an important maturation mediator for dendritic cells (DCs). However, increased PGE2 levels in the tumor exert immunosuppressive effects on DCs by signaling through two E-Prostanoid (EP) receptors: EP2 and EP4. Blocking EP-receptor signaling of PGE2 with antagonists is currently being investigated for clinical applications to enhance anti-tumor immunity. In this study, we investigated a new delivery approach by encapsulating EP2/EP4 antagonists in polymeric nanoparticles. The nanoparticles were characterized for size, antagonist loading, and release. The efficacy of the encapsulated antagonists to block PGE2 signaling was analyzed using monocyte-derived DCs (moDCs). The obtained nanoparticles were sized between 210 and 260 nm. The encapsulation efficacy of the EP2/EP4 antagonists was 20% and 17%, respectively, and was further increased with the co-encapsulation of both antagonists. The treatment of moDCs with co-encapsulation EP2/EP4 antagonists prevented PGE2-induced co-stimulatory marker expression. Even though both antagonists showed a burst release within 15 min at 37 °C, the nanoparticles executed the immunomodulatory effects on moDCs. In summary, we demonstrate the functionality of EP2/EP4 antagonist-loaded nanoparticles to overcome PGE2 modulation of moDCs.

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“…Moreover, a functional selectivity of synthetic and natural ligands of EP4 has been described given by their ligand-receptor affinity constants [ 26 ], which could explain the inequal effect observed among PGE 2 , and EP2 and EP4 receptors in H3 citrullination. Both EP2 and EP4 are G protein-coupled receptors, and their signaling pathway leads to an increase in intracellular cAMP through Gα s protein that increases the gene expression of NFκB complex components [ 27 ]; therefore, the NFκB signaling pathway is activated. In terms of stimulus, in our research, ionomycin significantly reduced NFκB phosphorylation; this result is in accordance with that previously reported by Brignall R et al, who described that ionomycin induced NFAT activation rather than NFκB activation [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Human Amniotic Membrane Mesenchymal Stem Cell-Synthesized PGE2 Exerts an Immunomodulatory Effect on Neutrophil Extracellular Trap in a PAD-4-Dependent Pathway through EP2 and EP4

Estúa-Acosta

Buentello-Volante

Magaña‐Guerrero

et al. 2022

Cells

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Human amniotic membrane mesenchymal stem cells (hAM-MSC) secrete a myriad of components with immunosuppressive activities. In the present research, we aimed to describe the effect of prostaglandin E2 (PGE2) secreted by hAM-MSCs on neutrophil extracellular trap (NET) release and to characterize the role of its receptors (EP2/EP4) in PAD-4 and NFkB activity in neutrophils. Human peripheral blood neutrophils were ionomycin-stimulated in the presence of hAM-MSC conditioned medium (CM) treated or not with the selective PGE2 inhibitor MF-63, PGE2, EP2/EP4 agonists, and the selective PAD-4 inhibitor GSK-484. NET release, PAD-4, and NFkB activation were analyzed. Ionomycin induced NET release, which was inhibited in the presence of hAM-MSC-CM, while CM from hAM-MSCs treated with MF-63 prevented NET release inhibition. PGE2 and EP2/EP4 agonists, and GSK-484 inhibited NET release. EP2/EP4 agonists and GSK-484 inhibited H3-citrullination but did not affect PAD-4 protein expression. Finally, PGE2 and EP2/EP4 agonists and GSK-484 increased NFkB phosphorylation. Taken together, these results suggest that hAM-MSC exert their immunomodulatory activities through PGE2, inhibiting NET release in a PAD-4-dependent pathway. This research proposes a new mechanism by which hAM-MSC exert their activities when modulating the innate immune response and inhibiting NET release.

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PGE2-EP2/EP4 signaling elicits immunosuppression by driving the mregDC-Treg axis in inflammatory tumor microenvironment

Cited by 62 publications

References 51 publications

Strategies to overcome DC dysregulation in the tumor microenvironment

Strategies to overcome DC dysregulation in the tumor microenvironment

Tailored PGE2 Immunomodulation of moDCs by Nano-Encapsulated EP2/EP4 Antagonists

Human Amniotic Membrane Mesenchymal Stem Cell-Synthesized PGE2 Exerts an Immunomodulatory Effect on Neutrophil Extracellular Trap in a PAD-4-Dependent Pathway through EP2 and EP4

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