Investigating the neutrophil-sensory neuron crosstalk in lung cancer

研究肺癌中的中性粒细胞-感觉神经元串扰

• 批准号: 10642437
• 负责人: Chengcheng Jin
• 金额: $ 50.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642437
• 关键词: Ablation; Afferent Neurons; Automobile Driving; Bacterial Infections; Biology; CD8-Positive T-Lymphocytes; Calcium; Cancer Patient; Cells; Cellular Immunology; Clinical; Communication; Coughing; Development; Foundations; Future; Genetic; Genetically Engineered Mouse; Goals; Human; Hypersensitivity; IL17 gene; Image; Immune; Immune response; Immune system; Immunofluorescence Immunologic; Immunotherapy; Inflammation; Investigation; Light; Literature; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Nerve; Nervous System; Neural Pathways; Neurites; Neuroimmune; Neurons; Neuropeptides; Neutrophil Infiltration; Nociception; Nociceptors; Pain; Peripheral Nerves; Phenotype; Play; Prognosis; Publishing; Research; Resistance; Role; Sensory; Shapes; Signal Transduction; Skin; Solid Neoplasm; Stimulus; Symptoms; T-Lymphocyte; TRPV1 gene; Technology; Testing; Time; Tissues; Tumor Immunity; Tumor-Derived; Work; anti-PD-1; cancer cell; cancer genetics; cancer initiation; cancer prevention; cancer therapy; cancer type; cellular targeting; cytotoxic CD8 T cells; immune checkpoint blockade; improved; in vitro Assay; in vivo; insight; interest; lung tumorigenesis; nerve supply; neural; neuronal circuitry; neutrophil; new therapeutic target; pharmacologic; preclinical efficacy; response; sensory mechanism; tool; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis

Many types of solid tumors are innervated by distinct branches of the nervous system that, like the immune system, sense and respond to internal and environmental stimuli. However, nerves have long been viewed as passive bystanders in cancer. It is poorly understood how the nervous system regulates the tumor-associated immune responses, and what factors in the tissue-specific microenvironment shape tumor innervation. Therefore, the overarching goal of our research is to develop an in-depth and broad understanding of neuro-immune interaction in cancer with a focus on the bi-directional crosstalk between the sensory neurons and the tumor microenvironment (TME), and to explore whether we can target such interactions for more effective cancer treatment. Of particular interest, lung-innervating nociceptors are specialized sensory neurons that control cough and pain, the most common clinical symptoms in lung cancer patients. While nociceptors were shown to regulate lung immune cells in allergy and bacterial infections, little is known about their roles in oncogenesis. Our central hypothesis is that nociceptive sensory neurons play a key role in promoting lung cancer development via cross-talking to the immune cells, particularly the tumor-associated IL-17+T cells and neutrophils. As such, targeting the nociceptive neural pathways can improve the cancer response to immunotherapy by reprogramming the tumor immune microenvironment. Experimentally, we will combine genetically engineered mouse models that faithfully reproduce the human lung adenocarcinoma with cutting-edge approaches in cellular immunology, cancer genetics, and functional manipulations of neuronal circuits. Specifically, we propose to test our central hypothesis by (1) establishing the role of tumor innervation by sensory neurons in lung cancer, (2) elucidating the mechanisms by which tumor innervation shapes the cancer-associated immune responses, (3) determining the pre-clinical efficacy of targeting the nociceptive neural pathway in combination with checkpoint-based immunotherapy. Our study will provide fundamental insights to the emerging yet poorly understood functions and regulatory mechanisms of the sensory nervous system in the TME, especially their role in cancer- associated immune responses. Furthermore, the conceptual and technological advances generated here will build the foundation for future investigations into neuro-immune interactions in additional cancer types, shedding light on sensory neural pathways and neuro-immune crosstalk that can serve as novel therapeutic targets for cancer prevention and treatment.

许多类型的实体瘤由神经系统的不同分支支配，如 免疫系统感知并响应内部和环境刺激。然而，神经 长期以来一直被视为癌症的被动旁观者。人们对神经质的人 系统调节肿瘤相关的免疫反应，以及组织特异性 微环境塑造肿瘤神经支配。因此，我们研究的首要目标是 发展对癌症中神经免疫相互作用的深入和广泛的理解，重点是 感觉神经元和肿瘤微环境之间的双向串扰 (TME)，并探索我们是否可以针对这种相互作用进行更有效的癌症治疗。 特别令人感兴趣的是，肺神经支配的伤害感受器是专门的感觉神经元， 咳嗽和疼痛是肺癌患者最常见的临床症状。当伤害感受器 在过敏症和细菌感染中调节肺免疫细胞，但对 它们在肿瘤发生中的作用我们的中心假设是，伤害性感觉神经元发挥作用， 通过与免疫细胞的相互作用，特别是 肿瘤相关IL-17+T细胞和中性粒细胞。因此，靶向伤害性神经元 通过重新编程肿瘤， 免疫微环境实验上，我们将联合收割机 使用尖端方法忠实再现人类肺腺癌的模型 在细胞免疫学、癌症遗传学和神经元回路的功能操纵方面。 具体来说，我们建议通过以下方式来检验我们的中心假设：（1）建立肿瘤的作用， 肺癌中感觉神经元的神经支配，（2）阐明肿瘤 神经支配塑造癌症相关的免疫反应，（3）确定临床前 靶向伤害性神经通路与基于检查点的 免疫疗法 我们的研究将为新兴但知之甚少的功能提供基本的见解， TME中感觉神经系统的调节机制，特别是它们在癌症中的作用- 相关的免疫反应。此外，概念和技术的进步 这将为未来研究神经免疫相互作用奠定基础 在其他癌症类型中，揭示了感觉神经通路和神经免疫通路， 串扰可以作为癌症预防和治疗的新的治疗靶点。