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

• 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
• 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

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.

项目摘要/摘要 为了最大化它们的生长和转移潜能，实体瘤促进肿瘤中新神经纤维的形成。 微环境(TME)。在口腔、前列腺癌、乳腺癌、胃癌、胰腺癌和其他癌症患者中，高密度的 TME中的神经纤维与不良的临床结果有关。我们证明了口腔癌细胞可以诱导一种独特的 TME中肿瘤相关神经元(TAN)的异质性组成。神经系统扮演着重要的角色 在组织的动态平衡和炎症反应中。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作用的神经癌症信号，以确定 治疗和克服免疫治疗耐药性的新靶点。我们的初步数据显示，神经元 通过免疫调节分子的表达直接与免疫细胞沟通，间接通过 旁分泌，肾上腺素能依赖的癌细胞信号。我们将在提议的项目中测试的总体假设是 TANS会诱导一种支持肿瘤进展的不良免疫反应。这些新形成的，重新编程的 TANS通过包括静止神经元转化在内的多步骤机制来调节免疫反应。 转化为萌芽细胞，可以渗透并与其他类型的细胞相互作用，释放肾上腺素能神经活性分子，以及 支持发展免疫抑制微环境。这些步骤中的每一步都可能促进肿瘤 进展和治疗耐药。这项拟议的研究具有创新性，因为它将利用 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 基于神经免疫串扰的癌症治疗新靶点的研究进展。这一交叉学科 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(阿米特和卡林)的两个特定目标的生物统计学。目标1：确定通过哪些机制 神经元依赖的癌细胞信号调节细胞毒性T细胞功能。我们将使用药理和基因 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 了解重新编程的神经元如何调节细胞毒性T细胞的抗肿瘤活性。破译晒黑是如何发挥两种作用的 肾上腺素能信号和免疫检查点表达对抗肿瘤免疫的激活和抑制作用 分别将使我们能够利用安全、负担得起和成熟的神经调节方法来克服 癌症中的免疫抑制。目的2：鉴定Tan胞外囊泡穿梭驱动因子miRNAs 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 基因组学方法，我们将研究免疫调节基因在TANS中依赖于miRNA的功能可塑性。 拟议研究的完成将为针对神经元机制的治疗策略铺平道路。 与免疫抑制和对免疫治疗的逆转耐药有关。针对这一点的治疗方法 肿瘤生物学的关键组成部分有望改善患者的生存、治疗反应和生活质量。