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Prostaglandin E₂ directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling.

ABSTRACT: Regulatory T (Treg) cells are essential for control of inflammatory processes by suppressing effector T-cell functions. The actions of PGE₂ on the development and function of Treg cells, particularly under inflammatory conditions, are debated. In this study, we employed pharmacological and genetic approaches to examine whether PGE₂ had a direct action on T cells to modulate de novo differentiation of Treg cells. We found that TGF-β-induced Foxp3 expression and iTreg cell differentiation in vitro is markedly inhibited by PGE₂ , which was mediated by the receptors EP2 and EP4. Mechanistically, PGE₂ -EP2/EP4 signalling interrupts TGF-β signalling during iTreg differentiation. Moreover, EP4 deficiency in T cells impaired iTreg cell differentiation in vivo. Thus, our results demonstrate that PGE₂ negatively regulates iTreg cell differentiation through a direct action on T cells, highlighting the potential for selectively targeting the PGE₂ -EP2/EP4 pathway to control T cell-mediated inflammation.

SUBMITTER: Goepp M

PROVIDER: S-EPMC8561111 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Prostaglandin E2 directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling.

Goepp Marie M Crittenden Siobhan S Zhou You Y Rossi Adriano G AG Narumiya Shuh S Yao Chengcan C

Immunology 20211001 4

Regulatory T (Treg) cells are essential for control of inflammatory processes by suppressing effector T-cell functions. The actions of PGE2 on the development and function of Treg cells, particularly under inflammatory conditions, are debated. In this study, we employed pharmacological and genetic approaches to examine whether PGE2 had a direct action on T cells to modulate de novo differentiation of Treg cells. We found that TGF-β-induced Foxp3 expression and iTreg cell d ...[more]

PMID: 34529833

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Project description:While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small-molecule antagonists of single EP receptors, the cyclooxygenase-2 (COX-2) inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous, and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8+ T cells in vitro as compared with single EP antagonists. CD8+ T-cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased tumor microenvironment lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC)min+/- spontaneous colorectal tumor model, compared with celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small-molecule dual EP2/EP4 antagonist.SignificanceProstaglandin (PGE2) drives tumor progression but the pathway has not been effectively drugged. We demonstrate significantly enhanced immunologic potency and antitumor activity through blockade of EP2 and EP4 PGE2 receptor signaling together with a single molecule.

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Prostaglandin E₂ directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling.

Publications

Prostaglandin E<sub>2</sub> directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling.

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Prostaglandin E2 directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling.

Publications

Prostaglandin E&lt;sub&gt;2&lt;/sub&gt; directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Prostaglandin E₂ directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling.

Prostaglandin E<sub>2</sub> directly inhibits the conversion of inducible regulatory T cells through EP2 and EP4 receptors via antagonizing TGF-β signalling.