Abstract 393: Nicotinamide phosphoribosyl transferase (NAMPT) inhibitors: novel modulators of antitumor immunity

Abstract

Abstract Nicotinamide phosphoribosyltransferase (NAMPT), an essential enzyme involved in NAD metabolism, is a pleiotropic player in cell signalling and is implicated in a number of diseases, including cancer, inflammatory and metabolic disorders. NAMPT inhibitors (e.g. FK866 and CHS828) have been shown to be potentially effective in cancer therapy and have entered clinical trials in oncology. NAMPT could represent a putative link between metabolism, inflammation and cancer. This study investigated the role of NAMPT in cancer-related inflammation. A mouse model of transplantable MNMCA1 fibrosarcoma was utilized. WT Mice or NAMPTflox CrelysM+/- mice were injected with 10^4 MN-MNCA1 or G217R MNMCA1 (NAMPT inhibitors resistant cell line) cells and subsequently treated or not with 10 mg/kg of NAMPT inhibitors. Next, tumor growth, metastasis formation, tumor angiogenesis and the inflammatory infiltrate were estimated. In addition, monocytic (M-MDSCs) and granulocytic (G-MDSCs) myeloid derived-suppressor cells (MDSCs), isolated from the spleen of tumour bearing mice (untreated and treated with NAMPT inhibitors), or differentiated in vitro from bone marrow precursors, were analysed for their suppressive activity, nitric oxide (NO) production, gene profile and expression of enzymes involved in cancer-associated immunosuppression (e.g. iNOS, ARG1, NOX2). In the fibrosarcoma mouse model, NAMPT inhibitors inhibited tumor growth, tumor vessel formation and delay metastasis formation. Phenotypic analysis of the immune infiltrate revealed that the number of macrophages and dendritic cells was not affected by NAMPT inhibition. However MDSCs displayed a marked decreased in blood, spleen and primary tumour, which was associated with an increase number of both CD4+ and CD8+ T lymphocytes. On the contrary an increase number of MDSCs have been found in the bone marrow. A detail analysis of CXCR4 expression revealed that NAMPT inhibitors affect MDSCs migration in vivo. Moreover, in NAMPTflox CrelysM+/- mice fibrosarcoma growth is reduced. Expression analysis revealed that NAMPT was up-regulated in MDSCs in response to M1-stimulation, suggesting a role of this enzyme during inflammatory process. Moreover, NAMPT inhibitors blocked the NO-mediated T cell suppressive activity induced by IFNγ in M-MDSC. Preliminary evidences indicate a role of both AMPK and SIRT 1/3 in the inhibition of M-MDSC suppressive activity operated by NAMPT inhibitors. Furthermore, both M-MDSCs isolated from spleen of NAMPT inhibitors treated mice and MDSCs isolated from NAMPTflox CrelysM+/- mice display a reduced T-cell suppression activity. Here, we demonstrate for the first time a role of NAMPT metabolism in the functional differentiation of suppressive M-MDSCs associated with cancer development and suggest that pharmacological inhibition of NAMPT may prevent cancer-associated immunosuppression, restoring adaptive antitumor immunity. Citation Format: Cristina Travelli, Sara Morlacchi, Ubaldina Galli, Gian Cesare Tron, Armando A Genazzani, Antonio Sica. Nicotinamide phosphoribosyl transferase (NAMPT) inhibitors: novel modulators of antitumor immunity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 393. doi:10.1158/1538-7445.AM2015-393