Nicotinamide Phosphoribosyltransferase (NAMPT) acts as a metabolic gate for mobilization of myeloid-derived suppressor cells

Cancer induces alteration of hematopoiesis to fuel disease progression. We report that in tumor-bearing mice the macrophage colony-stimulating factor (M-CSF) elevates the myeloid cell levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the nicotinamide adenine dinucleotide (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 HIF-1α-driven CXCR4 gene transcription, leading to mobilization of immature myeloid-derived suppressor cells (MDSCs) and enhancing their production of suppressive nitric oxide. Pharmacological inhibition or myeloid-specific ablation of NAMPT prevented MDSCs mobilization, reactivated specific antitumor immunity and enhanced the antitumor activity of immune checkpoint inhibitors. Our findings identify NAMPT as a metabolic gate of MDSCs precursor function, providing new opportunities to reverse tumor immunosuppression and restore clinical efficacy of immunotherapy in cancer patients.

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