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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要临床和实验证据表明，癌症进展取决于以下因素的相互作用：恶性细胞与肿瘤微环境（TME）的其他功能相关。成纤维细胞、内皮细胞、肿瘤浸润免疫细胞和其他调节肿瘤的基质成分周围神经元的生长和进展现在也被认为是。肿瘤环境的重要组成部分肿瘤神经支配的程度与癌症直接相关。进展和转移，并与患者生存呈负相关。已提出神经介导的癌症进展，包括神经递质的调节活性和神经肽对肿瘤相关脉管系统和免疫浸润的影响迄今为止，主要在这一领域开展工作。重点关注自主神经系统在促进癌症方面的作用，有几份报告也涉及然而，周围神经系统神经胶质细胞的作用。具体而言，排除神经周围浸润的过程，促进癌症进展仍不清楚。周围神经系统的主要神经胶质细胞雪旺细胞 (SC) 调节 TME 和我们尚未研究过 SC 是否存在于人体中。黑色素瘤组织，并且它们在几种黑色素瘤小鼠模型中加速肿瘤生长和转移。我们发现这种效应是由于修复 SC 的激活及其对三级淋巴的抑制然而，SC 的机制（TLS）形成和保护性抗肿瘤免疫反应。 TME 中的免疫调节仍然未知，我们勇敢地承认黑色素瘤相关的修复 SC。促进对黑色素瘤的免疫耐受，其靶向是一种针对黑色素瘤的新型免疫治疗方法为了检验我们的假设，我们将追求两个具体目标：1）确定癌症的机制。通过黑色素瘤中的修复 SC 进行免疫调节，以及 2）黑色素瘤中的靶向修复 SC 作为一种新方法在目标 1 中，我们将研究 SC 如何促进癌症的免疫耐受并阻碍 TLS。肿瘤中的形成，重点关注 Slit2、MAG 和 p75NTR 转基因信号机制。免疫活性的原生 BrafCA 黑色素瘤和慢华勒变性 WldS 小鼠模型在目标 2 中，我们将测试黑色素瘤相关修复 SC 是否会破坏免疫。耐受性与当前的抗 PD-1 和抗 CTLA4 疗法具有协同作用该提案的主要影响。将是 SC 依赖性免疫耐受维持的机制验证——一个重大挑战在目前晚期恶性肿瘤的治疗中，我们期望我们的结果将验证一种新颖的方法。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——这种方法将可能适用于其他类型的癌症。