4.8 Article

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

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CANCER RESEARCH
卷 79, 期 8, 页码 1938-1951

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-1544

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  1. Associazione Italiana Ricerca sul Cancro (AIRC) Program Innovative Tools for Cancer Risk Assessment and Diagnosis, 5 per mille [12162, 14194, 15585, 19885]
  2. AIRC, fellowship Pierluigi Meneghelli [19682]
  3. Leonino Fontana e Maria Lionello Fellowship [14832]
  4. SIF-Takeda grant in Pharmaceutical oncology
  5. Fondazione Veronesi Fellowship 2018
  6. Fondazione San Paolo, Dipartimento di Scienze del Farmaco, Universita del Piemonte Orientale, Novara
  7. Fondazione Cariplo
  8. Ministero Universita Ricerca (MIUR)

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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 HIF1 alpha-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.

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