Regulation of TIM-3 expression in a human T cell line by tumor-conditioned media and cyclic AMP-dependent signaling

Yun, Su Jin; Lee, Bokyoung; Komori, Kuniharu; Lee, Mi Jin; Lee, Byoung Gill; Kim, Kyongmin; Park, Sun

doi:10.1016/j.molimm.2018.12.006

Cited by 12 publications

(7 citation statements)

References 43 publications

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“…PGE2 has been shown to induce expression of cell-surface ectonucleases CD39 and CD73 on CD14 + monocytes (Al-Taei et al, 2017), resulting in production of adenosine is a breakdown product of ATP that mediates tumor progression and immunosuppression. PGE2 acting through the EP4 receptor has been shown to induce the immune checkpoint protein TIM3 on Jurkat T cells (Yun et al, 2019). Mesenchymal stem cells (MSC) from tumors selectively inhibited the function of NK cells in tumors, and this is mediated by PGE2 production by the MSC (Galland et al, 2017).…”

Section: Role Of Prostaglandinsmentioning

confidence: 99%

Eicosanoids in Cancer: New Roles in Immunoregulation

2020

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Eicosanoids represent a family of active biolipids derived from arachidonic acid primarily through the action of cytosolic phospholipase A2-α. Three major downstream pathways have been defined: the cyclooxygenase (COX) pathway which produces prostaglandins and thromboxanes; the 5-lipoxygenase pathway (5-LO), which produces leukotrienes, lipoxins and hydroxyeicosatetraenoic acids, and the cytochrome P450 pathway which produces epoxygenated fatty acids. In general, these lipid mediators are released and act in an autocrine or paracrine fashion through binding to cell surface receptors. The pattern of eicosanoid production is cell specific, and is determined by cell-specific expression of downstream synthases. Increased eicosanoid production is associated with inflammation and a panel of specific inhibitors have been developed designated non-steroidal anti-inflammatory drugs. In cancer, eicosanoids are produced both by tumor cells as well as cells of the tumor microenvironment. Earlier studies demonstrated that prostaglandin E2, produced through the action of COX-2, promoted cancer cell proliferation and metastasis in multiple cancers. This resulted in the development of COX-2 inhibitors as potential therapeutic agents. However, cardiac toxicities associated with these agents limited their use as therapeutic agents. The advent of immunotherapy, especially the use of immune checkpoint inhibitors has revolutionized cancer treatment in multiple malignancies. However, the majority of patients do not respond to these agents as monotherapy, leading to intense investigation of other pathways mediating immunosuppression in order to develop rational combination therapies. Recent data have indicated that PGE2 has immunosuppressive activity, leading to renewed interest in targeting this pathway. However, little is known regarding the role of other eicosanoids in modulating the tumor microenvironment, and regulating anti-tumor immunity. This article reviews the role of eicosanoids in cancer, with a focus on their role in modulating the tumor microenvironment. While the role of PGE2 will be discussed, data implicating other eicosanoids, especially products produced through the lipoxygenase and cytochrome P450 pathway will be examined. The existence of small molecular inhibitors and activators of eicosanoid pathways such as specific receptor blockers make them attractive candidates for therapeutic trials, especially in combination with novel immunotherapies such as immune checkpoint inhibitors.

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Section: Role Of Prostaglandinsmentioning

confidence: 99%

Eicosanoids in Cancer: New Roles in Immunoregulation

2020

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“…Although the mechanism of Tim3 induction by Adrb2 signaling was not clarified in detail, we at least confirmed that Tim3 expression induced by Adrb2 activation was dependent on PKA signaling (canonical downstream component of Adrb2 signaling) in macrophages (Figure 2C). As cAMP/ PKA signaling is reported to induce promoter/enhancer activity of Tim3 in Jurkat T cells, 31 the induction of Tim3 in macrophages may also be explained by promoter/enhancer activity.…”

Section: Discussionmentioning

confidence: 98%

Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury

Hasegawa

Inoue

Nakamura

et al. 2021

JASN

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BackgroundThe sympathetic nervous system regulates immune cell dynamics. However, the detailed role of sympathetic signaling in inflammatory diseases is still unclear because it varies according to the disease situation and responsible cell types. This study focused on identifying the functions of sympathetic signaling in macrophages in LPS-induced sepsis and renal ischemia-reperfusion injury (IRI).MethodsWe performed RNA sequencing of mouse macrophage cell lines to identify the critical gene that mediates the anti-inflammatory effect of β2-adrenergic receptor (Adrb2) signaling. We also examined the effects of salbutamol (a selective Adrb2 agonist) in LPS-induced systemic inflammation and renal IRI. Macrophage-specific Adrb2 conditional knockout (cKO) mice and the adoptive transfer of salbutamol-treated macrophages were used to assess the involvement of macrophage Adrb2 signaling.ResultsIn vitro, activation of Adrb2 signaling in macrophages induced the expression of T cell Ig and mucin domain 3 (Tim3), which contributes to anti-inflammatory phenotypic alterations. In vivo, salbutamol administration blocked LPS-induced systemic inflammation and protected against renal IRI; this protection was mitigated in macrophage-specific Adrb2 cKO mice. The adoptive transfer of salbutamol-treated macrophages also protected against renal IRI. Single-cell RNA sequencing revealed that this protection was associated with the accumulation of Tim3-expressing macrophages in the renal tissue.ConclusionsThe activation of Adrb2 signaling in macrophages induces anti-inflammatory phenotypic alterations partially via the induction of Tim3 expression, which blocks LPS-induced systemic inflammation and protects against renal IRI.

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“…PGE 2 /EP4 signaling increases cAMP production (52). One study has previously shown that the PGE 2 /EP4/cAMP upregulates the expression of T cell Ig and mucin domain-3 (TIM-3), an immunoinhibitory molecule, in a human T cell line (53). Additionally, several reports have investigated that TIM-3 expression is induced after the PD-1/PD-L1 blockade, leading to the resistance to PD-1/PD-L1 blockade (39,50).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Immunotherapeutic Efficacy of Anti–PD-L1 Antibody in Combination with an EP4 Antagonist

et al. 2020

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Combination treatment approaches are increasingly considered to overcome resistance to immunotherapy targeting immunoinhibitory molecules such as programmed death (PD)-1 and PD-ligand 1 (PD-L1). Previous studies have demonstrated that the therapeutic efficacy of anti-PD-L1 Abs is enhanced by combination treatment with cyclooxygenase-2 inhibitors, through downregulation of the immunosuppressive eicosanoid PGE 2 , although the underlying mechanism remains unclear. In this study, we show that serum PGE 2 levels are upregulated after anti-PD-L1 Ab administration in a bovine model of immunotherapy and that PGE 2 directly inhibits T cell activation via its receptor E prostanoid (EP) 4. Additionally, anti-PD-L1 Ab induces TNF-a production and TNF-a blockade reduces PGE 2 production in the presence of anti-PD-L1 Ab, suggesting that anti-PD-L1 Ab-induced TNF-a impairs T cell activation by PGE 2 upregulation. Our studies examining the therapeutic potential of the dual blockade of PD-L1 and EP4 in bovine and murine immune cells reveal that the dual blockade of PD-L1 and EP4 significantly enhances Th1 cytokine production in vitro. Finally, we show that the dual blockade decreases tumor volume and prolongs survival in mice inoculated with the murine lymphoma cell line EG7. Altogether, these results suggest that TNF-a induced by anti-PD-L1 Ab treatment is associated with T cell dysfunction via PGE 2 /EP4 pathway and that the dual blockade of PD-L1 and EP4 should be considered as a novel immunotherapy for cancer.

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Regulation of TIM-3 expression in a human T cell line by tumor-conditioned media and cyclic AMP-dependent signaling

Cited by 12 publications

References 43 publications

Eicosanoids in Cancer: New Roles in Immunoregulation

Eicosanoids in Cancer: New Roles in Immunoregulation

Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury

Enhanced Immunotherapeutic Efficacy of Anti–PD-L1 Antibody in Combination with an EP4 Antagonist

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