Tumor-Derived Prostaglandin E2 Promotes p50 NF-κB-Dependent Differentiation of Monocytic MDSCs

Porta, Chiara; Consonni, Francesca Maria; Morlacchi, Sara; Sangaletti, Sabina; Bleve, Augusto; Totaro, Maria Grazia; Larghi, Paola; Rimoldi, Monica; Tripodo, Claudio; Strauss, Laura; Banfi, Stefania; Storto, Mariangela; Pressiani, Tiziana; Rimassa, Lorenza; Tartari, Silvia; Ippolito, Alessandro; Doni, Andrea; Soldà, Giulia; Duga, Stefano; Piccolo, Viviana; Ostuni, Renato; Natoli, Gioacchino; Bronte, Vincenzo; Balzac, Fiorella; Turco, Emilia; Hirsch, Emilio; Colombo, Mario P.; Sica, Antonio

doi:10.1158/0008-5472.can-19-2843

Cited by 98 publications

(79 citation statements)

References 55 publications

(73 reference statements)

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“…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). These effects are mediated through nuclear accumulation of p50 NF-κB, and production of nitric oxide (NO).…”

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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“…In both type of diseases, the rapid myelopoiesis of myeloid cells at the BM is likely to be directed by several cytokines and transcription factors, among them interleukin-17A (IL-17A) ROR1C that induces IL-17A, G-CSF, GM-CSF, TNFa and others (2,4,6,14,37,38), whereas maintenance of the suppressive function is driven by several components that affect the activities of MDSC at the tumor site, including interaction with other cells, particularly T cells cytokines, chemokines, and transcription factors, and the effect of microRNA released from exosomes (39)(40)(41).…”

Section: The Two-stage Model Of Myeloid Cells Mobilization and Functionmentioning

confidence: 99%

The Development and Homing of Myeloid-Derived Suppressor Cells: From a Two-Stage Model to a Multistep Narrative

Karin

2020

Front. Immunol.

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Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of immature myeloid cells. Under normal conditions, they differentiate into macrophages, dendritic cells, and granulocytes. Under pathological conditions, such as chronic inflammation, or cancer, they tend to maintain their immature state as immature myeloid cells that, within the tumor microenvironment, become suppressor cells and assist tumor escape from immune eradication. MDSC are comprised of two major subsets: monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC). Monocytic myeloid cells give rise to monocytic cells, whereas PMN-MDSC share similarities with neutrophils. Based on their biological activities, a two-stage model that includes the mobilization of the periphery as myeloid cells and their activation within the tumor microenvironment converting them into suppressor cells was previously suggested by D. Gabrilovich. From the migratory viewpoint, we are suggesting a more complex setup. It starts with crosstalk between the tumor site and the hematopoietic stem and progenitor cells (HSPCs) at the bone marrow (BM) and secondary lymphatic organs, resulting in rapid myelopoiesis followed by mobilization to the blood. Although myelopoiesis is coordinated by several cytokines and transcription factors, mobilization is selectively directed by chemokine receptors and may differ between M-MDSC and PMN-MDSC. These myeloid cells may then undergo further expansion at these secondary lymphatic organs and then home to the tumor site. Finally, selective homing of T cell subsets has been associated with retention at the target organs directed by adhesion molecules or chemokine receptors. The possible relevance to myeloid cells is still speculative but is discussed.

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“…Among the factors mediating tumor-induced reprogramming of monocytes, PGE2 appears to be a promising candidate for therapeutic targeting. A PGE2 receptor 2 (EP2) antagonist (AH6809) prevented PGE2-induced NF-κB activation and subsequent Nos2 expression in splenic and tumor-infiltrating monocytes, reducing their immunosuppressive activity and leading to an enhanced antitumor T-cell response in mouse models (132).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Systemic Reprogramming of Monocytes in Cancer

et al. 2020

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Monocytes influence multiple aspects of tumor progression, including antitumor immunity, angiogenesis, and metastasis, primarily by infiltrating tumors, and differentiating into tumor-associated macrophages. Emerging evidence suggests that the tumor-induced systemic environment influences the development and phenotype of monocytes before their arrival to the tumor site. As a result, circulating monocytes show functional alterations in cancer, such as the acquisition of immunosuppressive activity and reduced responsiveness to inflammatory stimuli. In this review, we summarize available evidence about cancer-induced changes in monopoiesis and its impact on the abundance and function of monocytes in the periphery. In addition, we describe the phenotypical alterations observed in tumor-educated peripheral blood monocytes and highlight crucial gaps in our knowledge about additional cellular functions that may be affected based on transcriptomic studies. We also highlight emerging therapeutic strategies that aim to reverse cancer-induced changes in monopoiesis and peripheral monocytes to inhibit tumor progression and improve therapy responses. Overall, we suggest that an in-depth understanding of systemic monocyte reprogramming will have implications for cancer immunotherapy and the development of clinical biomarkers.

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Tumor-Derived Prostaglandin E2 Promotes p50 NF-κB-Dependent Differentiation of Monocytic MDSCs

Cited by 98 publications

References 55 publications

Eicosanoids in Cancer: New Roles in Immunoregulation

Eicosanoids in Cancer: New Roles in Immunoregulation

The Development and Homing of Myeloid-Derived Suppressor Cells: From a Two-Stage Model to a Multistep Narrative

Systemic Reprogramming of Monocytes in Cancer

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