TY - JOUR
T1 - Nicotinamide phosphoribosyltransferase acts as a metabolic gate for mobilization of myeloid-derived suppressor cells
AU - Travelli, Cristina
AU - Consonni, Francesca Maria
AU - Sangaletti, Sabina
AU - Storto, Mariangela
AU - Morlacchi, Sara
AU - Grolla, Ambra A.
AU - Galli, Ubaldina
AU - Tron, Gian Cesare
AU - Portararo, Paola
AU - Rimassa, Lorenza
AU - Pressiani, Tiziana
AU - Mazzone, Massimiliano
AU - Trovato, Rosalinda
AU - Ugel, Stefano
AU - Bronte, Vincenzo
AU - Tripodo, Claudio
AU - Colombo, Mario P.
AU - Genazzani, Armando A.
AU - Sica, Antonio
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/4/15
Y1 - 2019/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064461877&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-1544
DO - 10.1158/0008-5472.CAN-18-1544
M3 - Article
SN - 0008-5472
VL - 79
SP - 1938
EP - 1951
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -
