Nicotinamide phosphoribosyltransferase acts as a metabolic gate for mobilization of myeloid-derived suppressor cells

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

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)1938-1951
Number of pages14
JournalCancer Research
Volume79
Issue number8
DOIs
Publication statusPublished - Apr 15 2019

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