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

项目摘要 免疫细胞渗入肿瘤微环境(TME)并分泌炎性细胞因子，如 干扰素(IFN)，以推动抗肿瘤反应和肿瘤清除(1)。I型和II型IFN具有长 已知可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来促进生长和肿瘤负担(2，5)。我们的 初步数据表明，干扰素γ信号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和黑色素瘤 与健康细胞相比，细胞的NAMPT表达增加。NAMPT对黑色素瘤细胞的抑制作用 显著减少增殖(7-9)。我们的初步数据表明，干扰素γ激活上调NAMPT在 人和小鼠黑色素瘤，我们发现干扰素γ诱导的NAMPT对黑色素瘤细胞的生长至关重要。 活着。此外，I型干扰素，干扰素β，也可以上调黑色素瘤细胞中的NAMPT。干扰素基因刺激物 (STING)激动剂促进干扰素β表达和免疫细胞向三叉神经节细胞的渗透以增强抗肿瘤作用 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(SIRT1)和哺乳动物的Target of 雷帕霉素(MTOR)，我们将研究这些途径是否介导了干扰素-1的增殖效应。 诱导型NAMPT。我们的工作假设是NAMPT介导了肿瘤对抗增殖剂的耐药性 干扰素和以干扰素为基础的免疫治疗的效果，如刺痛激动剂治疗 促进SIRT1和mTOR信令。我们将通过完成以下目标来研究我们的假设： 目的1：了解干扰素诱导的NAMPT促进黑色素瘤生长的机制 生长 目的2：研究干扰素诱导的NAMPT的两个下游靶标SIRT1和mTOR的作用。 关于黑色素瘤生长的研究 这项资助的目的是阐明干扰素诱导的NAMPT在肿瘤中驱动免疫逃避的机制 细胞。这项提议将为改善免疫治疗结果铺平道路，通过将 作为NAMPT抑制剂、刺痛激动剂和其他下游免疫调节剂。将拟议的工作统称为 将首次让我们深入了解代谢基因NAMPT在小鼠和小鼠体内的促肿瘤作用 人黑色素瘤体内生长免疫治疗的研究。

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.