6533b872fe1ef96bd12d397f
RESEARCH PRODUCT
Nicotinamide Phosphoribosyltransferase Acts as a Metabolic Gate for Mobilization of Myeloid-Derived Suppressor Cells
Vincenzo BronteGian Cesare TronMario P. ColomboFrancesca Maria ConsonniUbaldina GalliMassimiliano MazzoneAmbra A. GrollaTiziana PressianiSabina SangalettiClaudio TripodoSara MorlacchiMariangela StortoRosalinda TrovatoCristina TravelliCristina TravelliAntonio SicaAntonio SicaPaola PortararoStefano UgelArmando A. GenazzaniLorenza Rimassasubject
0301 basic medicineCancer ResearchMyeloidmedicine.medical_treatmentNudeNicotinamide phosphoribosyltransferaseApoptosisColorectal NeoplasmInbred C57BLMicechemistry.chemical_compound0302 clinical medicineTumor Cells CulturedHematopoiesiNicotinamide PhosphoribosyltransferaseInbred BALB CMice Inbred BALB CCulturedbiologySarcomaTumor CellsHaematopoiesismedicine.anatomical_structureOncology030220 oncology & carcinogenesisSirtuinFemaleSarcoma ExperimentalColorectal NeoplasmsAnimals; Apoptosis; Cell Proliferation; Colorectal Neoplasms; Female; Hematopoiesis; Humans; Mammary Neoplasms Experimental; Mice; Mice Inbred BALB C; Mice Inbred C57BL; Mice Nude; Myeloid-Derived Suppressor Cells; NAD; Nicotinamide Phosphoribosyltransferase; Sarcoma Experimental; Signal Transduction; Tumor Cells Cultured; Xenograft Model Antitumor AssaysHumanSignal TransductionMice NudeExperimental03 medical and health sciencesmedicineMyeloid-Derived Suppressor CellAnimalsHumansCell ProliferationAnimalMyeloid-Derived Suppressor CellsMammary NeoplasmsApoptosiMammary Neoplasms ExperimentalImmunotherapyNADXenograft Model Antitumor AssaysHematopoiesisMice Inbred C57BL030104 developmental biologychemistrybiology.proteinCancer researchMyeloid-derived Suppressor CellNAD+ kinaseBone marrowdescription
Abstract Cancer induces alteration of hematopoiesis to fuel disease progression. We report that in tumor-bearing mice the macrophage colony-stimulating factor elevates the myeloid cell levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway, which acts as negative regulator of the CXCR4 retention axis of hematopoietic cells in the bone marrow. NAMPT inhibits CXCR4 through a NAD/Sirtuin 1–mediated inactivation of HIF1α-driven CXCR4 gene transcription, leading to mobilization of immature myeloid-derived suppressor cells (MDSC) and enhancing their production of suppressive nitric oxide. Pharmacologic inhibition or myeloid-specific ablation of NAMPT prevented MDSC mobilization, reactivated specific antitumor immunity, and enhanced the antitumor activity of immune checkpoint inhibitors. Our findings identify NAMPT as a metabolic gate of MDSC precursor function, providing new opportunities to reverse tumor immunosuppression and to restore clinical efficacy of immunotherapy in patients with cancer. Significance: These findings identify NAMPT as a metabolic gate of MDSC precursor function, providing new opportunities to reverse tumor immunosuppression and to restore clinical efficacy of immunotherapy in cancer patients.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-01-01 | Cancer Research |