Harnessing the nervous system to overcome resistance to immunotherapy in oral cancer

利用神经系统克服口腔癌免疫治疗的耐药性

基本信息

批准号：
10671578
负责人：
Moran Amit
金额：
$ 67.84万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671578
关键词：
Ablation Address Adrenergic Agents Afferent Neurons Axon Biological Models Biometry Breast Cancer Biology Cancer Patient Cell physiology Cells Cellular Structures Cellular biology Clinical Communication Complex Cues Cytotoxic T-Lymphocytes Data Development Environment Epithelium Equilibrium Event Genes Genetically Engineered Mouse Genomic approach Goals Growth Head and Neck Squamous Cell Carcinoma Homeostasis Human Imaging Techniques Immune Immune Evasion Immune response Immune signaling Immune system Immunologic Surveillance Immunology Immunosuppression Immunotherapy Infiltration Inflammatory Response Knowledge Malignant Neoplasms Mediating MicroRNAs Molecular Nerve Nerve Fibers Nervous System Neurobiology Neuroepithelial, Perineurial, and Schwann Cell Neoplasm Neuroimmune Neurons Oncology Operative Surgical Procedures Oral Outcome PD-1 blockade Pancreas Pathology Patients Peripheral Nervous System Persons Play Population Positioning Attribute Pre-Clinical Model Prostate Proteins Quality of life RNA Research Research Personnel Resistance Role Signal Induction Signal Transduction Solid Neoplasm Stomach T-Lymphocyte Testing Therapeutic Time Tissues Transcript Transcriptional Activation Tumor Biology Tumor Promotion Tumor Subtype Tumor-Derived Work calin cancer cell cancer genetics cancer therapy candidate identification cell type extracellular vesicles functional genomics functional plasticity genetic approach immune activation immune checkpoint immune checkpoint blockade immunoregulation improved in vitro activity innovation insight malignant mouth neoplasm molecular imaging mouse model mouth squamous cell carcinoma neoplastic cell nerve supply neural neuromechanism neuron loss neuroregulation neurotransmission neurotransmitter release new therapeutic target novel therapeutic intervention oral cavity epithelium oral tissue paracrine pharmacologic prevent programs recruit response success targeted cancer therapy targeted treatment therapy development therapy resistant transcriptomics treatment response treatment strategy tumor tumor microenvironment tumor progression tumor-immune system interactions tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT To maximize their growth and metastatic potential, solid tumors promote the formation of new nerve fibers in the tumor microenvironment (TME). In patients with oral, prostate, breast, gastric, pancreatic, and other cancers, high densities of nerve fibers in the TME are associated with poor clinical outcomes. We proved that oral cancer cells induce a unique heterogeneous composition of tumor-associated neurons (TANs) in the TME. The nervous system plays important roles in homeostasis and inflammatory responses in tissues. However, the regulation of immune cells by nerves remains largely unclear. Our long-term goal is to elucidate the reciprocal nerve-cancer signals that drive cancer progression to identify novel targets for therapy and for overcoming immunotherapy resistance. Our preliminary data show that neurons communicate with immune cells directly through the expression of immunomodulatory molecules and indirectly through paracrine, adrenergic-dependent cancer cell signaling. The overall hypothesis that we will test in the proposed project is that TANs induce a maladaptive immune response that supports tumor progression. These newly formed, reprogrammed TANs regulate the immune response through a multistep mechanism that includes the transformation of quiescent neurons into sprouting cells that can infiltrate and interact with other cell types, release adrenergic neuroactive molecules, and support the development of an immunosuppressive microenvironment. Each of these steps may promote tumor progression and therapy resistance. The proposed research is innovative because it will capitalize on new concepts in immunology and cancer biology using advanced model systems to yield insights into the mechanisms of tumor progression and identify new targets for cancer therapy based on neuro-immune crosstalk. This cross-disciplinary proposal will combine expertise from oncology, immunology, cell biology, neurobiology, cancer genetics, pathology, and biostatistics in two specific aims across the two labs (Amit and Calin). Aim 1: Determine the mechanisms by which neuron-dependent cancer cell signaling regulates cytotoxic T-cell function. We will use pharmacological and genetic approaches combined with advanced spatial imaging techniques (for both protein and RNA) in syngeneic mouse models to understand how reprogrammed neurons regulate cytotoxic T-cell antitumor activity. Deciphering how TANs exert both antitumor immune activation and suppression activity through adrenergic signaling and immune checkpoint expression respectively, will allow us to leverage safe, affordable and well established neuromodulatory approaches to overcome immunosuppression in cancer. Aim 2: Identify the extracellular vesicle-shuttled driver miRNAs of TAN reprogramming and their roles in oral cancer progression. Using human-derived sensory neurons and functional genomic approaches, we will investigate the miRNA-dependent functional plasticity of immunomodulatory genes in TANs. The completion of the proposed studies will pave the way for treatment strategies that target the neuronal mechanisms associated with immunosuppression and reverse resistance to immunotherapy. Therapeutic approaches targeting this critical component of tumor biology are anticipated to improve patients' survival, treatment responses, and quality of life.

项目概要/摘要为了最大限度地提高其生长和转移潜力，实体瘤促进肿瘤中新神经纤维的形成微环境（TME）。在患有口腔癌、前列腺癌、乳腺癌、胃癌、胰腺癌和其他癌症的患者中，高密度的 TME 中的神经纤维与不良的临床结果相关。我们证明口腔癌细胞会诱导一种独特的 TME 中肿瘤相关神经元 (TAN) 的异质组成。神经系统发挥重要作用组织中的稳态和炎症反应。然而，神经对免疫细胞的调节在很大程度上仍然存在不清楚。我们的长期目标是阐明驱动癌症进展的相互神经癌信号，以确定治疗和克服免疫治疗耐药性的新靶点。我们的初步数据表明神经元通过免疫调节分子的表达直接与免疫细胞沟通，并通过免疫细胞间接沟通旁分泌、肾上腺素依赖性癌细胞信号传导。我们将在拟议项目中测试的总体假设是 TAN 会诱导适应不良的免疫反应，从而支持肿瘤进展。这些新形成的、重新编程的 TAN 通过多步骤机制调节免疫反应，其中包括静态神经元的转化进入萌芽细胞，这些细胞可以渗透并与其他细胞类型相互作用，释放肾上腺素能神经活性分子，并且支持免疫抑制微环境的发展。这些步骤中的每一个都可能促进肿瘤进展和治疗抵抗。拟议的研究具有创新性，因为它将利用新概念免疫学和癌症生物学使用先进的模型系统来深入了解肿瘤的机制进展并根据神经免疫串扰确定癌症治疗的新靶点。这个跨学科该提案将结合肿瘤学、免疫学、细胞生物学、神经生物学、癌症遗传学、病理学和两个实验室（Amit 和 Calin）的两个特定目标的生物统计学。目标 1：确定机制神经元依赖性癌细胞信号传导调节细胞毒性 T 细胞功能。我们将利用药理学和遗传学在同基因小鼠模型中结合先进的空间成像技术（蛋白质和 RNA）的方法了解重编程神经元如何调节细胞毒性 T 细胞抗肿瘤活性。解读 TAN 如何发挥这两种作用通过肾上腺素信号传导和免疫检查点表达来激活和抑制抗肿瘤免疫活性分别将使我们能够利用安全、负担得起且完善的神经调节方法来克服癌症中的免疫抑制。目标 2：鉴定 TAN 的细胞外囊泡穿梭驱动 miRNA 重编程及其在口腔癌进展中的作用。使用人类来源的感觉神经元和功能通过基因组方法，我们将研究 TAN 中免疫调节基因的 miRNA 依赖性功能可塑性。拟议研究的完成将为针对神经机制的治疗策略铺平道路与免疫抑制和逆转免疫治疗耐药性有关。针对此的治疗方法肿瘤生物学的关键组成部分预计将改善患者的生存、治疗反应和生活质量。