Nicotinamide Phosphoribosyltransferase Acts as a Metabolic Gate for Mobilization of Myeloid-Derived Suppressor Cells

Travelli, Cristina; Consonni, Francesca Maria; Sangaletti, Sabina; Storto, Mariangela; Morlacchi, Sara; Grolla, Ambra A.; Galli, Ubaldina; Tron, Gian Cesare; Portararo, Paola; Rimassa, Lorenza; Pressiani, Tiziana; Mazzone, Massimiliano; Trovato, Rosalinda; Ugel, Stefano; Bronte, Vincenzo; Tripodo, Claudio; Colombo, Mario P.; Genazzani, Armando A.; Sica, Antonio

doi:10.1158/0008-5472.can-18-1544

Cited by 65 publications

(62 citation statements)

References 41 publications

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“…Recently, it was demonstrated that iNAMPT acts also on myeloid-derived suppressor cells (MDSCs), where NAMPT blocks CXCR4 transcription, via a SIRT1/HIF-1α axis. The activation of this circuit, in turn, leads to MDSCs mobilization and enhances the production of nitric oxide, promoting immunosuppression (149).…”

Section: Enampt/enaprt In Myeloid Cells Function: the Role Of Tlr4mentioning

confidence: 99%

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

2020

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Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT) are two intracellular enzymes that catalyze the first step in the biosynthesis of NAD from nicotinamide and nicotinic acid, respectively. By fine tuning intracellular NAD levels, they are involved in the regulation/reprogramming of cellular metabolism and in the control of the activity of NAD-dependent enzymes, including sirtuins, PARPs, and NADases. However, during evolution they both acquired novel functions as extracellular endogenous mediators of inflammation. It is well-known that cellular stress and/or damage induce release in the extracellular milieu of endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs), which modulate immune functions through binding pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), and activate inflammatory responses. Increasing evidence suggests that extracellular (e)NAMPT and eNAPRT are novel soluble factors with cytokine/adipokine/DAMP-like actions. Elevated eNAMPT were reported in several metabolic and inflammatory disorders, including obesity, diabetes, and cancer, while eNAPRT is emerging as a biomarker of sepsis and septic shock. This review will discuss available data concerning the dual role of this unique family of enzymes.

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Section: Enampt/enaprt In Myeloid Cells Function: the Role Of Tlr4mentioning

confidence: 99%

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

2020

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“…Consequently, low CXCR4 resulted in mobilization of immature myeloid-derived suppressor cells (MDSCs), contributing to tumor immunosuppression. Importantly, pharmacologic inhibition of NAMPT resulted in a decrease in MDSC mobilization, reversing the immunosuppression and re-sensitizing tumor cells to immunotherapeutic agents in preclinical models (142).…”

Section: Immune Regulation Of Tumor Microenvironmentmentioning

confidence: 99%

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Heske

2020

Front. Oncol.

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Tumor cells have increased requirements for NAD +. Thus, many cancers exhibit an increased reliance on NAD + production pathways. This dependence may be exploited therapeutically through pharmacological targeting of NAMPT, the rate-limiting enzyme in the NAD + salvage pathway. Despite promising preclinical data using NAMPT inhibitors in cancer models, early NAMPT inhibitors showed limited efficacy in several early phase clinical trials, necessitating the identification of strategies, such as drug combinations, to enhance their efficacy. While the effect of NAMPT inhibitors on impairment of energy metabolism in cancer cells has been well-described, more recent insights have uncovered a number of additional targetable cellular processes that are impacted by inhibition of NAMPT. These include sirtuin function, DNA repair machinery, redox homeostasis, molecular signaling, cellular stemness, and immune processes. This review highlights the recent findings describing the effects of NAMPT inhibitors on the non-metabolic functions of malignant cells, with a focus on how this information can be leveraged clinically. Combining NAMPT inhibitors with other therapies that target NAD +-dependent processes or selecting tumors with specific vulnerabilities that can be co-targeted with NAMPT inhibitors may represent opportunities to exploit the multiple functions of this enzyme for greater therapeutic benefit.

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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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Nicotinamide Phosphoribosyltransferase Acts as a Metabolic Gate for Mobilization of Myeloid-Derived Suppressor Cells

Cited by 65 publications

References 41 publications

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

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

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