Format

Send to

Choose Destination
Cancer Res. 2019 Apr 15;79(8):1938-1951. doi: 10.1158/0008-5472.CAN-18-1544. Epub 2019 Feb 18.

Nicotinamide Phosphoribosyltransferase Acts as a Metabolic Gate for Mobilization of Myeloid-Derived Suppressor Cells.

Author information

1
Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy.
2
Department of Pharmaceutical Sciences, University of Pavia, Pavia, Italy.
3
Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
4
Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
5
Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
6
Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, Vesalius Research Center, VIB, Leuven, Belgium.
7
Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
8
Human Pathology Section, Department of Health Sciences, University of Palermo, Palermo, Italy.
9
Tumor and Microenvironment Histopathology Unit, the FIRC Institute of Molecular Medicine (IFOM), Milan, Italy.
10
Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy. antonio.sica@uniupo.it armando.genazzani@uniupo.it.

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.

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Miscellaneous

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center