Dissecting Neuro-Immune Interactions in Cancer

项目摘要/摘要：癌症非常擅长利用正常的生理功能 支持其发展。组织生理学的一个重要组成部分是神经元，它在我们的 器官，释放神经肽到附近的组织。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不为人所知和研究不足。我们的初步分析表明，肿瘤 渗入的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有关。这些数据表明 神经支配可能在抗肿瘤免疫调节中发挥重要作用。为了检验这一假设，我们建议 研究神经支配在癌症中的作用并确定神经肽感觉如何在癌症中的作用的策略 免疫细胞在以下方面影响抗肿瘤免疫： 肿瘤神经衰弱的研究目的：(1)研究肿瘤中感觉神经元的神经支配程度(2) 确定树突状细胞上的神经肽感应如何影响抗肿瘤免疫反应。 使用报告工具和多路成像，我们将在临床前确定肿瘤组织的神经支配 模特和病人样本。在我们结果的基础上，我们将研究功能和转录 使用内源性和同源模型研究神经肽感觉对免疫群体的影响。 这个项目的结果有可能极大地提高我们目前对神经质的理解。 系统对癌症的贡献。在治疗上，利用现有的癌症神经元的脆弱性 临床批准的神经调节剂有可能迅速转化为临床预防和治疗 癌症的治疗。这项由NCI资助的跨学科研究的遗产将是理解神经- 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、肿瘤神经科学、树突状细胞、神经免疫 互动 图形摘要：在几种肿瘤中，肿瘤神经支配与生存不良有关。我提议学习 皮肤和肺肿瘤中的神经元密度，并质疑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，包括作用于感受器的CGRP 表达树突状细胞(DC)。总之，这会导致钝化的DC反应使CD8+T细胞永久化 功能障碍和肿瘤进展。 目标1 目标2

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