NGF recruits nerve fibers to reprogram an immunosuppressive microenvironment in melanoma

神经浸润与几种实体肿瘤类型的形成和发展有关 包括前列腺癌、胃癌和胰腺癌。然而，尽管黑色素瘤源于神经，但它 神经支配以前没有报道过。在我们的初步研究中，我们发现黑色素瘤 来自患者样本和小鼠模型的肿瘤组织受到高度神经支配。这种神经支配是 依赖于肿瘤细胞神经生长因子(NGF)的表达，因为靶向NGF耗竭消除 瘤内神经纤维。重要的是，黑色素瘤通过NGF基因敲除或化学物质来失神经 交感神经切除术通过重塑肿瘤微环境(TME)显著减轻肿瘤负担。 这种TME重编程与细胞因子和趋化因子表达增加有关，CD103+DC 激活和CD8+T细胞募集，表明NGF或神经源性神经递质支持 通过抑制抗肿瘤免疫来促进肿瘤生长。重要的是，我们确认了这种负相关性。 在肿瘤神经支配和炎症之间使用临床样本：黑色素瘤表达低水平的 NGF是免疫学上的热点，与改善患者的存活率有关。这些发现启发了我们 可以利用NGF介导的肿瘤微环境神经支配的中心假说 药理上可以逆转免疫抑制。在这项研究中，我们将使用 以下三个目标：目标1将剖析NGF介导的血管重塑的分子机制 瘤内免疫微环境。目标2将剖析NGF调节的分子机制 T细胞活化。目标3将确定结合神经生长因子的治疗策略的临床前疗效 轴抑制和免疫检查点阻断黑色素瘤。拟议研究的结果 将为开发潜在的联合疗法来对抗这种疾病奠定基础 疾病。

Nerve infiltration has been implicated in the formation and progression of several solid tumor types including prostate, gastric, and pancreatic cancers. However, despite its neural origin, melanoma innervation has not been previously reported. In our preliminary studies, we discovered that melanoma tumor tissues from patient samples and mouse models are highly innervated. This innervation is dependent on tumor cell expression of nerve growth factor (NGF), as targeted NGF depletion eliminates intratumoral nerve fibers. Importantly, melanoma denervation via NGF knockdown or chemical sympathectomy dramatically reduces tumor burdens by remodeling the tumor microenvironment (TME). This TME reprogramming is associated with increased cytokine and chemokine expression, CD103+ DC activation, and CD8+ T cell recruitment, suggesting that NGF or nerve-derived neurotransmitters support tumor growth by suppressing antitumor immunity. Importantly, we confirmed this inverse correlation between tumor innervation and inflammation using clinical samples: melanomas expressing low levels of NGF are immunologically hot and associated with improved patient survival. These findings inspire our central hypothesis that NGF-mediated innervation of the tumor microenvironment can be exploited pharmacologically to reverse immunosuppression. In this study, we will test this hypothesis with the following three aims: Aim 1 will dissect molecular mechanisms of NGF-mediated remodeling of the intratumor immune microenvironment. Aim 2 will dissect molecular mechanisms by which NGF regulates T cell activation. Aim 3 will determine the pre-clinical efficacy of a therapeutic strategy combining NGF axis inhibition and immune checkpoint blockade against melanoma. Findings from the proposed studies will lay the foundation upon which potential combinational therapies can be developed to combat this disease.