NGF recruits nerve fibers to reprogram an immunosuppressive microenvironment in melanoma

NGF 招募神经纤维来重新编程黑色素瘤中的免疫抑制微环境

基本信息

批准号：
10552544
负责人：
XIAO-FAN WANG
金额：
$ 49.45万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552544
关键词：
Adrenergic beta-Antagonists Biological Biological Markers CD8-Positive T-Lymphocytes CTLA4 gene Catecholamines Cells Chemical Sympathectomy Clinical Combined Modality Therapy Consensus Cross Presentation Dendritic Cells Dendritic cell activation Denervation Disease Disease remission Exclusion Foundations Genes Immune system Immunologic Factors Immunologic Stimulation Immunosuppression Immunotherapy Individual Infiltration Inflammation Interferon Type I Interferons Interleukin-12 Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Mediating Modeling Molecular Natural Killer Cells Nerve Nerve Fibers Nerve Growth Factors Neural Crest Neurons Neurotransmitters Norepinephrine Pancreas Pathway interactions Patients Physiological Population Propranolol Prospective Studies Prostate Receptor Signaling Recurrence Reporting Resistance Risk Reduction Role Sampling Shapes Signal Transduction Solid Neoplasm Source Stomach T-Cell Activation T-Lymphocyte T-cell inflamed Testing Therapeutic Tumor Antigens Tumor Burden Tumor Escape Tumor Immunity Tumor Tissue anti-tumor immune response beta-adrenergic receptor cancer cell cancer immunotherapy cancer therapy chemokine combat cytokine effector T cell immune checkpoint blockade improved knock-down malignant stomach neoplasm melanocyte melanoma mouse model neoplastic cell nerve supply neural novel novel therapeutic intervention pharmacologic preclinical efficacy programmed cell death protein 1 programs recruit response success tumor tumor growth tumor microenvironment tumor-immune system interactions

项目摘要

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.

神经浸润与多种实体瘤类型的形成和进展有关包括前列腺癌、胃癌和胰腺癌。然而，尽管黑色素瘤具有神经起源，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神经生长因子 (NGF) 的肿瘤细胞表达，因为靶向 NGF 耗竭可消除瘤内神经纤维。重要的是，通过 NGF 敲低或化学药物来去除黑色素瘤神经交感神经切除术通过重塑肿瘤微环境（TME）来显着减轻肿瘤负荷。这种 TME 重编程与细胞因子和趋化因子表达增加相关，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抑制肿瘤生长。重要的是，我们证实了这种逆相关性使用临床样本研究肿瘤神经支配和炎症之间的关系：表达低水平的黑色素瘤 NGF 具有免疫热效应，与改善患者生存率相关。这些发现启发我们中心假设是可以利用 NGF 介导的肿瘤微环境神经支配药理学上逆转免疫抑制。在本研究中，我们将用以下三个目标：目标 1 将剖析 NGF 介导的神经细胞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 细胞激活。目标 3 将确定结合 NGF 的治疗策略的临床前疗效轴抑制和免疫检查点阻断对抗黑色素瘤。拟议研究的结果将为开发潜在的联合疗法来对抗这一问题奠定基础疾病。