Melanoma NAMPT mediates resistance to the anti-proliferative effects of Interferons (IFNs) and IFN based immunotherapies such as STING Agonists

工程摘要 免疫细胞浸润肿瘤微环境（TME）并分泌炎性细胞因子，如 干扰素（IFN），以驱动抗肿瘤反应和肿瘤清除（1）。I型和II型IFN具有长 已知其减少肿瘤生长并具有显著的抗增殖作用。然而，最近的证据表明， 表明肿瘤细胞也可以利用IFN以增强生长和肿瘤负荷（2，5）。我们 初步数据表明，IFNγ信号传导的一个结果是烟酰胺磷酸核糖基转移酶（Nampt） 上调。Nampt是NAD+合成的限速酶（6）。所有细胞都利用Nampt， 与健康细胞相比，细胞表现出增加的Nampt表达。黑素瘤细胞中的Nampt抑制 显著降低增殖（7-9）。我们的初步数据表明，IFNγ激活上调Nampt， 在人类和小鼠黑色素瘤中，我们发现IFNγ诱导的Nampt对黑色素瘤细胞的生长至关重要， vivo.此外，I型IFN，IFNβ，也可以上调黑素瘤细胞中的Nampt。IFN基因刺激因子 （STING）激动剂促进IFNβ表达和免疫细胞浸润到TME中以改善抗肿瘤作用。 免疫治疗期间的反应。然而，它们也可能通过促进肿瘤NAMPT而促进肿瘤生长。 表情最后，Nampt可以通过sirtuin 1（SIRT 1）和哺乳动物靶蛋白来调节细胞过程。 雷帕霉素（mTOR），我们将研究这些途径是否介导IFN-γ的增殖作用。 诱导型纳米粒子我们的工作假设是，Nampt介导肿瘤对抗增殖抑制剂的耐药性。 干扰素（IFN）和基于IFN的免疫疗法（如STING激动剂治疗）的作用 促进SIRT 1和mTOR信号传导。我们将通过完成以下目标来研究我们的假设： 目的1：了解IFN诱导的Nampt促进黑色素瘤发生的机制 增长 目的2：研究IFN诱导的Nampt的两个下游靶点SIRT 1和mTOR的作用， 黑色素瘤的生长 该基金的目的是阐明IFN诱导的Nampt在肿瘤中驱动免疫逃避的机制 细胞该提案将为通过组合化合物， 作为Nampt抑制剂、STING激动剂和其它下游免疫调节剂。总体而言，拟议工作 这将首次让我们深入了解代谢基因Nampt在小鼠中的促肿瘤作用， 在免疫治疗的背景下体内人黑素瘤肿瘤生长。

Project Abstract Immune cells infiltrate the tumor microenvironment (TME) and secrete inflammatory cytokines such as interferons (IFNs) in order to drive anti-tumor responses and tumor clearance(1). Type I and II IFNs have long been known to reduce tumor growth and to have significant anti-proliferative effects. However, recent evidence suggests that tumor cells can also harness IFNs in order to enhance growth and tumor burden(2, 5). Our preliminary data indicate that one outcome of IFNγ signaling is nicotinamide phosphoribosyltransferase (Nampt) upregulation. Nampt is the rate-limiting enzyme in NAD+ synthesis(6). All cells utilize Nampt, and melanoma cells exhibit increased Nampt expression compared to healthy cells. Nampt inhibition in melanoma cells significantly reduces proliferation(7-9). Our preliminary data indicate that IFNγ activation upregulates Nampt in both human and mouse melanoma, and we show that IFNγ-inducible Nampt is vital for melanoma cell growth in vivo. Additionally, a Type I IFN, IFNβ, can also upregulate Nampt in melanoma cells. Stimulator of IFN Genes (STING) agonists promote IFNβ expression and immune cell infiltration into the TME to improve anti-tumor responses during immunotherapies. However, they may also promote tumor growth by promoting tumor NAMPT expression. Lastly, Nampt can regulate cellular processes through sirtuin 1 (SIRT1) and mammalian Target of Rapamycin (mTOR), and we will investigate whether these pathways mediate the proliferative effect of IFN- inducible Nampt. Our working hypothesis is that Nampt mediates tumor resistance to the anti-proliferative effects of Interferons (IFNs) and IFN-based immunotherapies such as STING agonist treatment by promoting SIRT1 and mTOR signaling. We will investigate our hypothesis by completing the following aims: Aim 1: Understand the mechanisms by which IFN-inducible Nampt promotes melanoma tumor growth Aim 2: Investigate the role of two downstream targets of IFN-inducible Nampt, SIRT1 and mTOR, on melanoma growth The objective of this grant is to elucidate mechanisms of immune evasion driven by IFN-inducible Nampt in tumor cells. This proposal will pave the way for improving immunotherapy outcomes by combining compounds such as Nampt inhibitors, STING agonists, and other downstream immune modulators. Collectively the proposed work will, for the first time, give us insight into the pro-tumorigenic role of the metabolic gene, Nampt, in mouse and human melanoma tumor growth in vivo in the context of immunotherapy.