Dissecting Neuro-Immune Interactions in Cancer

剖析癌症中的神经免疫相互作用

• 批准号: 10722350
• 负责人: Karen Olivia Dixon
• 金额: $ 14.32万
• 依托单位: UNIVERSITY OF BASEL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722350
• 关键词: Ablation; Affect; Afferent Neurons; Antigen Presentation; CD8-Positive T-Lymphocytes; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cells; Clinical; Colon Adenocarcinoma; Colorectal Cancer; Communication; Cross Presentation; Data; Dendritic Cells; Disease; Experimental Models; Fostering; Functional disorder; Funding; Gene Expression; Genetic Transcription; Growth; Health; Immune; Immune response; Immune system; Immunotherapy; Inflammation; Infrastructure; Interdisciplinary Study; Knowledge; Lung Neoplasms; Malignant Neoplasms; Modeling; Neoplasm Metastasis; Nerve; Nervous System; Neurogenic Inflammation; Neuroimmune; Neuroimmunomodulation; Neuromodulator; Neurons; Neuropeptide Receptor; Neuropeptides; Neurosciences; Neurosciences Research; Nociceptors; Normal tissue morphology; Organ; Pancreas; Pathogenesis; Pathway interactions; Patients; Peripheral; Physiological; Physiology; Play; Population; Pre-Clinical Model; Prevention; Process; Prostate; Reporter; Reporting; Research; Role; Sampling; Sensory; Sensory Receptors; Shapes; Skin Neoplasms; Stimulus; T-Lymphocyte; TRPV1 gene; Testing; Therapeutic; Tissues; Translating; Tumor Antigens; Tumor Burden; Tumor Immunity; Tumor Markers; Tumor Promotion; Tumor Tissue; Tumor-infiltrating immune cells; Work; anti-tumor immune response; anticancer research; cancer cell; cancer therapy; cytokine; density; design; draining lymph node; immunoregulation; malignant stomach neoplasm; multiplexed imaging; nerve supply; novel; novel therapeutic intervention; receptor; recruit; response; systemic inflammatory response; tool; treatment response; tumor; tumor immunology; tumor initiation; tumor microenvironment; tumor progression

PROJECT SUMMARY/ABSTRACT: Cancer is highly adept at exploiting normal physiological functions to support its growth. One important component of tissue physiology is neurons which weave through our organs, releasing neuropeptides into nearby tissue. Importantly, the role innervation plays in malignancy and anti-tumor immunity remains largely unknown and understudied. Our preliminary analysis shows that tumor infiltrating immune cells express high levels of receptors for sensory neuropeptides, which further positively correlates with expression of genes associated with immune cell dysfunction. These data suggest that innervation may play an important role in regulating anti-tumor immunity. To test this hypothesis, we propose strategies to investigate the role of innervation in cancer, and to determine how neuropeptide sensing on immune cells impacts anti-tumor immunity in the following objectives: Objectives of Unnerving Cancer: (1) Investigate the degree of sensory neuron innervation in cancer (2) Determine how neuropeptide sensing on DCs impacts anti- tumor immune responses. Using reporter tools and multiplexed imaging, we will determine innervation of tumor tissues in pre-clinical models and patient samples. Building on our results, we will investigate the functional and transcriptional effects of neuropeptide sensing on immune populations using endogenous and syngeneic models. Results from this project have the potential to significantly advance our current understanding of the nervous system's contribution to cancer. Therapeutically, exploiting the neuronal vulnerability of cancer using existing clinically approved neuromodulators has the potential to rapidly translate clinically for the prevention and treatment of cancer. The legacy of this NCI funded interdisciplinary research will be to understand the neuro- immune communication in cancer, opening doors for novel therapeutic strategies. Keywords: Tumor Immunology, Immunotherapy, Cancer Neuroscience, Dendritic cells, Neuro-Immune Interactions Graphical Abstract: Tumor innervation correlates with poor survival in several tumours. I propose to study neuronal density in Skin and Lung tumour, and query correlation of neuronal density to therapeutic responses. I hypothesise that Sensory Neurons release neuropeptides, including CGRP, which acts on receptor expressing dendritic cells (DCs). Together this leads to blunted DC responses perpetuating CD8+ T cell dysfunction and tumor progression. Objective 1 Objective 2

项目摘要/摘要：癌症非常善于利用正常的生理功能来 支持其成长。组织生理学的一个重要组成部分是神经元，它穿过我们的 器官，将神经肽释放到附近的组织中。重要的是，神经支配在恶性肿瘤和 抗肿瘤免疫在很大程度上仍然未知且未被充分研究。我们的初步分析表明，肿瘤 浸润免疫细胞表达高水平的感觉神经肽受体，这进一步积极 与免疫细胞功能障碍相关基因的表达相关。这些数据表明 神经支配可能在调节抗肿瘤免疫中发挥重要作用。为了检验这个假设，我们提出 研究神经支配在癌症中的作用，并确定神经肽传感如何影响癌症的策略 免疫细胞通过以下目标影响抗肿瘤免疫力： 令人不安的癌症的目标：(1) 研究癌症中感觉神经元神经支配的程度 (2) 确定 DC 上的神经肽感应如何影响抗肿瘤免疫反应。 使用报告工具和多重成像，我们将在临床前确定肿瘤组织的神经支配 模型和患者样本。基于我们的结果，我们将研究功能和转录 使用内源性和同基因模型神经肽传感对免疫群体的影响。 该项目的结果有可能显着增进我们目前对神经的理解 系统对癌症的贡献。在治疗上，利用现有的方法利用癌症的神经元脆弱性 临床批准的神经调节剂有可能快速转化为临床用于预防和治疗 癌症的治疗。这项 NCI 资助的跨学科研究的遗产将是了解神经 癌症中的免疫通讯，为新的治疗策略打开了大门。 关键词：肿瘤免疫学、免疫治疗、癌症神经科学、树突状细胞、神经免疫 互动 图解摘要：肿瘤神经支配与多种肿瘤的不良生存相关。我建议学习 皮肤和肺肿瘤中的神经元密度，并查询神经元密度与治疗反应的相关性。 我假设感觉神经元释放神经肽，包括作用于受体的 CGRP 表达树突状细胞（DC）。这共同导致 DC 反应减弱，使 CD8+ T 细胞永久存在 功能障碍和肿瘤进展。 目标1 目标2