PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model

Wang, Tong; Jing, Bo; Xu, Danfeng; Liao, Yueling; Song, Hui; Sun, Beibei; Guo, Wenzheng; Xu, Jin; Li, Kaimi; Hu, Min; Liu, Shuli; Jing, Ling; Kuang, Yanbin; Zhang, Tuo; Zhang, Siwei; Yao, Feng; Zhou, Binhua P.; Deng, Jiong

doi:10.1038/s41388-020-1207-6

Cited by 56 publications

(44 citation statements)

References 48 publications

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“…Simultaneously, clinical, and epidemiological data have indicated that prolonged COX‐PGE 2 inhibition with NSAIDs at high dosages is associated with an increased risk of gastrointestinal and cardiovascular events compared with non‐NSAIDs (Mukherjee et al , 2001; Wang & Dubois, 2006; Sostres et al , 2010). Recently, Deng et al reported that a prostaglandin E Synthase inhibitor (Cay10526) suppressed tumor malignant progression in a spontaneous lung adenocarcinoma model (Wang et al , 2020); however, its clinical benefits require further investigation. To date, several EP4 antagonists have entered human clinical trials for the treatment of migraine, inflammatory diseases, and cancer.…”

Section: Discussionmentioning

confidence: 99%

Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer

Lü

et al. 2020

EMBO Mol Med

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Immune checkpoint blockade (ICB) has a limited effect on colorectal cancer, underlining the requirement of co-targeting the complementary mechanisms. Here, we identified prostaglandin E2 (PGE 2) receptor 4 (EP4) as the master regulator of immunosuppressive myeloid cells (IMCs), which are the major driver of resistance to ICB therapy. PGE 2-bound EP4 promotes the differentiation of immunosuppressive M2 macrophages and myeloid-derived suppressor cells (MDSCs) and reduces the expansion of immunostimulated M1 macrophages. To explore the immunotherapeutic role of EP4 signaling, we developed a novel and selective EP4 antagonist TP-16. TP-16 effectively blocked the function of IMCs and enhanced cytotoxic T-cellmediated tumor elimination in vivo. Cell co-culture experiments revealed that TP-16 promoted T-cell proliferation, which was impaired by tumor-derived CD11b + myeloid cells. Notably, TP-16 and anti-PD-1 combination therapy significantly impeded tumor progression and prolonged mice survival. We further demonstrated that TP-16 increased responsiveness to anti-PD-1 therapy in an IMC-related spontaneous colorectal cancer mouse model. In summary, this study demonstrates that inhibition of EP4-expressing IMCs may offer a potential strategy for enhancing the efficacy of immunotherapy for colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer

Lü

et al. 2020

EMBO Mol Med

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“…Prostaglandin E 2 (PGE 2 ) is a key proinflammatory PG. PGE 2 upregulated TAMs and MDSCs contributed to immunosuppression and EMT-mediated lung metastasis to mouse lungs [53]. Apart from modulating EMT, PGE 2 derived from COX-2 induced expression of MIR675-5p, which inhibited p53 and promoted CRC metastasis [54].…”

Section: Eicosanoidsmentioning

confidence: 99%

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

et al. 2020

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Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.

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“…MDSCs act to suppress the anti-tumoral activity of T cells and other cell types (Veglia et al, 2018). In a lung cancer model in which Gprc5a is deleted, increased PGE2 synthesis was also associated with recruitment of MDSCs as well as promotion of alternatively activated M2 macrophages (Wang et al, 2020). PGE2 has been shown to signal through the EP2 receptor to induce an immunosuppressive phenotype in MDSC (Porta et al, 2020).…”

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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PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model

Cited by 56 publications

References 48 publications

Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer

Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

Eicosanoids in Cancer: New Roles in Immunoregulation

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