Nicotinamide phosphoribosyltransferase acts as a metabolic gate for mobilization of myeloid-derived suppressor cells
- Authors: Travelli C.; Consonni F.M.; Sangaletti S.; Storto M.; Morlacchi S.; Grolla A.A.; Galli U.; Tron G.C.; Portararo P.; Rimassa L.; Pressiani T.; Mazzone M.; Trovato R.; Ugel S.; Bronte V.; Tripodo C.; Colombo M.P.; Genazzani A.A.; Sica A.
- Publication year: 2019
- Type: Articolo in rivista
- OA Link: http://hdl.handle.net/10447/395202
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 HIF1a-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.