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

• 批准号: 10321215
• 负责人: XIAO-FAN WANG
• 金额: $ 49.42万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 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/10321215
• 关键词: Adrenergic beta-Antagonists; Biological; Biological Markers; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Catecholamines; Cells; Chemical Sympathectomy; Clinical; Combined Modality Therapy; Consensus; Dendritic Cells; Dendritic cell activation; Denervation; Disease; Exclusion; Foundations; Immune; Immune system; Immunologic Factors; Immunosuppression; 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; Neurons; Neurotransmitters; Norepinephrine; Pathway interactions; Patients; Pharmacology; Physiological; Population; Propranolol; Prospective Studies; Receptor Signaling; Reporting; Resistance; Risk Reduction; Role; Sampling; Shapes; Solid Neoplasm; Source; T-Cell Activation; T-Lymphocyte; T-cell inflamed; Testing; Therapeutic; Tumor Antigens; Tumor Burden; Tumor Immunity; Tumor Tissue; anti-tumor immune response; beta-adrenergic receptor; cancer cell; cancer immunotherapy; cancer therapy; chemokine; combat; cytokine; immune checkpoint blockade; improved; knock-down; malignant stomach neoplasm; melanocyte; melanoma; mouse model; neoplastic cell; nerve supply; novel; novel therapeutic intervention; preclinical efficacy; programmed cell death protein 1; recruit; relating to nervous system; response; success; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

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.

神经浸润与几种实体瘤的形成和发展有关