The Role of Schwann Cells in the Progression of Melanoma

雪旺细胞在黑色素瘤进展中的作用

• 批准号: 10574973
• 负责人: Yuri Bunimovich
• 金额: $ 45.32万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574973
• 关键词: Acceleration; Area; Autoimmune; Autonomic nervous system; Cancer Model; Cell Therapy; Cells; Cellular biology; Clinical; Communication; Elements; Endothelial Cells; Exclusion; Extracellular Matrix; Fibroblasts; Human; Immune; Immune Tolerance; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunooncology; Immunosuppression; Immunotherapy; Inflammatory; Invaded; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Molecular; Multiple Sclerosis; NGFR Protein; Natural regeneration; Neoplasm Metastasis; Nerve; Neurodegenerative Disorders; Neuroglia; Neurons; Neuropathy; Neuropeptides; Neurotransmitters; Pain; Patients; Peripheral; Peripheral Nervous System; Play; Process; Property; Publishing; Regulation; Reporting; Research; Role; Schwann Cells; Signal Transduction; Spinal cord injury; Syndrome; Testing; Tissues; Transgenic Organisms; Treatment Failure; Tumor Immunity; Tumor-Associated Vasculature; Tumor-infiltrating immune cells; Wallerian Degeneration; Work; anti-CTLA-4 therapy; anti-CTLA4; anti-PD-1; anti-tumor immune response; cancer cell; cancer therapy; cancer type; clinically relevant; evidence base; expectation; falls; immune cell infiltrate; immunoregulation; improved; malignant breast neoplasm; melanoma; mouse model; nerve repair; nerve supply; novel; novel strategies; novel therapeutic intervention; perineural; pharmacologic; prevent; promoter; repaired; response; synergism; targeted treatment; tertiary lymphoid organ; tissue repair; translational oncology; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression

Project Summary Clinical and experimental evidence demonstrate that cancer progression depends on the interactions of malignant cells with other elements of the tumor microenvironment (TME). Functions of cancer-associated fibroblasts, endothelial cells, tumor-infiltrating immune cells and other stromal elements in regulating tumor growth and progression have been intensively investigated. Peripheral neurons are now also recognized as important constituents of the tumor milieu. The degree of tumor innervation is directly correlated with cancer progression and metastasis, and inversely correlated with patient survival. Several mechanisms responsible for nerve-mediated cancer progression have been proposed, including regulatory activity of neurotransmitters and neuropeptides on tumor-associated vasculature and immune infiltrate. Thus far, work in this area largely focused on the role of the autonomic nervous system in promoting cancer, with several reports also implicating the somatic afferent innervation. However, the role of the neuroglia of the peripheral nervous system in promoting cancer progression remains unclear. Specifically, excluding the process of perineural invasion, the extent to which Schwann cells (SCs), principal glia of the peripheral nervous system, modulate TME and facilitate cancer progression has not been investigated. We demonstrated that SCs are present in human melanoma tissue, and that they accelerate tumor growth and metastasis in several melanoma mouse models. We discovered that this effect is due to the activation of repair SCs, and their inhibition of tertiary lymphoid structure (TLS) formation and protective anti-tumor immune responses. However, the mechanism of SC immunomodulation in TME remains unknown. We hypothesize that melanoma-associated repair SCs promote immune tolerance to melanoma, and their targeting is a novel immunotherapy approach against cancer. To test our hypothesis, we will pursue two Specific Aims: 1) determine the mechanism of immunomodulation by repair SCs in melanoma, and 2) target repair SCs in melanoma as a novel approach to therapy. In Aim 1, we will examine how SCs promote immune tolerance of cancer and impede TLS formation in tumors, focusing on Slit2, MAG, and p75NTR signaling mechanisms. Transgenic immunocompetent autochthonous BrafCA melanoma and slow Wallerian degeneration WldS mouse models will be utilized. In Aim 2, we will test whether targeting melanoma-associated repair SCs to break immune tolerance synergizes with current anti-PD-1 and anti-CTLA4 therapies. The primary impact of the proposal will be mechanistic verification of SC-dependent maintenance of the immune tolerance – a major challenge in the current treatment of advanced malignancies. We expect that our results will validate a novel immunotherapy approach for melanoma based on targeting tumor-associated glia – an approach which will likely be applicable to other types of cancer.

项目摘要 临床和实验证据表明，癌症的进展取决于以下因素的相互作用： 恶性肿瘤细胞与肿瘤微环境（TME）的其他元素。癌症相关的功能 成纤维细胞、内皮细胞、肿瘤浸润免疫细胞和其他基质成分在调节肿瘤中的作用 已经深入研究了生长和进展。外周神经元现在也被认为是 肿瘤环境的重要组成部分。肿瘤神经支配的程度与癌变直接相关 进展和转移，并与患者生存率呈负相关。负责的几个机制 已经提出了神经介导的癌症进展，包括神经递质的调节活性 以及神经肽对肿瘤相关血管和免疫浸润的影响。到目前为止，这方面的工作主要是 集中在自主神经系统在促进癌症中的作用，有几份报告也暗示， 躯体传入神经支配然而，周围神经系统的神经胶质细胞在 促进癌症进展仍不清楚。具体地说，排除神经周围侵入的过程， 雪旺细胞（SC），周围神经系统的主要胶质细胞，调节TME的程度， 促进癌症进展尚未研究。我们证明，SC存在于人类， 在一些黑色素瘤小鼠模型中，它们加速肿瘤生长和转移。 我们发现这种效应是由于修复SC的激活，以及它们对三级淋巴细胞的抑制， 结构（TLS）形成和保护性抗肿瘤免疫应答。然而，SC的机制 TME中的免疫调节仍然未知。我们假设黑色素瘤相关修复SC 促进对黑色素瘤的免疫耐受，它们的靶向是一种新的免疫治疗方法， 癌为了验证我们的假设，我们将追求两个具体目标：1）确定 通过修复黑色素瘤中的SC进行免疫调节，以及2）靶向修复黑色素瘤中的SC作为一种新方法 接受治疗在目标1中，我们将研究SC如何促进癌症的免疫耐受并阻止TLS 肿瘤形成，重点是Slit 2，MAG和p75 NTR信号传导机制。转基因 免疫活性自体BrafCA黑色素瘤和缓慢Wallerian变性WldS小鼠模型 将被利用。在目标2中，我们将测试是否靶向黑色素瘤相关的修复SC，以破坏免疫反应。 耐受性与目前的抗PD-1和抗CTLA 4疗法协同作用。提案的主要影响 将是SC依赖性免疫耐受维持的机制验证-这是一个重大挑战 在目前治疗晚期恶性肿瘤的过程中。我们希望我们的结果将验证一种新的 基于靶向肿瘤相关神经胶质细胞的黑色素瘤免疫治疗方法-一种将 可能适用于其他类型的癌症。