Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia

Abstract

Key Points• CLL lymphocytes show high intracellular and extracellular NAMPT levels, further increased upon activation.• eNAMPT prompts differentiation of CLL monocytes into M2 macrophages that sustain CLL survival and reduce T-cell proliferation.Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in nicotinamide adenine dinucleotide biosynthesis. In the extracellular compartment, it exhibits cytokine-/adipokinelike properties, suggesting that it stands at the crossroad between metabolism and inflammation. Here we show that both intracellular and extracellular NAMPT levels are increased in cells and plasma of chronic lymphocytic leukemia (CLL) patients. The extracellular form (eNAMPT) is produced by CLL lymphocytes upon B-cell receptor, Toll-like receptor, and nuclear factor kB (NF-kB) signaling pathway activation. eNAMPT is important for differentiation of resting monocytes, polarizing them toward tumor-supporting M2 macrophages. These cells express high levels of CD163, CD206, and indoleamine 2,3-dioxygenase and secrete immunosuppressive (interleukin [IL] 10, CC chemokine ligand 18) and tumor-promoting (IL-6, IL-8) cytokines. NAMPT-primed M2 macrophages activate extracellular-regulated kinase 1/2, signal transducer and activator of transcription 3, and NF-kB signaling; promote leukemic cell survival; and reduce T-cell responses. These effects are independent of the enzymatic activity of NAMPT, as inferred from the use of an enzymatically inactive mutant. Overall, these results reveal that eNAMPT is a critical element in the induction of an immunosuppressive and tumor-promoting microenvironment of CLL. (Blood. 2015;125(1):111-123) IntroductionBesides being the first line of defense against pathogens, macrophages orchestrate tissue plasticity and homeostasis. They are classified into classically activated (M1) or alternatively activated (M2) macrophages, reflecting a different functional role. 1 In cancer tissues, macrophages tend to be of the M2 phenotype, acquired and maintained through multiple interactions with tumor cells.2 Evidence indicates that these macrophages enhance tumor progression, mainly through the secretion of chemokines/cytokines that sustain neoplastic the cell proliferation and suppress immune responses. 3,4 Chronic lymphocytic leukemia (CLL) is a disease of mature B cells, which rely on the host environment for progression. [5][6][7] Tumor-host interactions occur predominantly in protected niches in the lymph nodes (LNs) and in the bone marrow, known as proliferation centers. 8,9 Within these areas, CLL cells are in contact with a population of CD681 elements, resembling tumor-associated macrophages. [10][11][12][13] They may be also differentiated in vitro by coculturing peripheral blood monocytes with CLL cells. These so-called nurselike cells (NLCs) protect leukemic cells from apoptosis through multiple interactions regulated by soluble or cell-surface-anchored molecules. 14,15 Leukemic cells play an essential role in driving NLC differentiation, as inferred fr...

Organ-Specific Microenvironment Modifies Diverse Functional and Phenotypic Characteristics of Leukemia-Associated Macrophages in Mouse T Cell Acute Lymphoblastic Leukemia

“…Macrophages in the myeloma microenvironment were suggested to protect myeloma cells from chemotherapy drug-induced apoptosis (42). Most recently, Audrito et al (43) demonstrated that extracellular nicotinamide phosphoribosyltransferase promoted M2 macrophage polarization in chronic lymphocytic leukemia. However, the distribution and the phenotypic features of macrophages in different organs during the development of hematopoietic malignancies have not been established.…”

Physiological and pathophysiological roles of NAMPT and NAD metabolism

“…157,158 Clinical studies have demonstrated that serum or blood levels of eNAMPT are increased in patients with cancer and a positive correlation exists between either tissue or eNAMPT levels and the stage of cancer progression. [159][160][161][162][163] However, the molecular pathways of eNAMPT signalling in carcinogenesis are far from clear. eNAMPT affects redox adaptive responses and promotes tumour proliferation in human malignant melanoma cells, 164 and influences resting monocytes, polarizing them towards a tumour-supporting M2 macrophage phenotype.…”

Increased plasma nicotinamide phosphoribosyltransferase is associated with a hyperproliferative phenotype and restrains disease progression in MPN‐associated myelofibrosis

“…In the tumor microenvironment, e-NAMPT induces monocyte polarization to M2 macrophages secreting tumor-promoting cytokines and inhibiting T-cell responses rendering this pleiotropic molecule a novel player in tumor/host cross-talk [27][28][29].…”