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，例如 免疫系统感知并响应内部和环境刺激。然而，神经 长期以来，人们一直被视为癌症的被动旁观者。人们对神经如何紧张的了解甚少 系统调节肿瘤相关的免疫反应，以及哪些因素影响组织特异性 微环境塑造肿瘤神经支配。因此，我们研究的总体目标是 重点发展对癌症神经免疫相互作用的深入和广泛的了解 感觉神经元与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来进行更有效的癌症治疗。 特别有趣的是，肺支配的伤害感受器是专门的感觉神经元，控制 咳嗽和疼痛是肺癌患者最常见的临床症状。虽然伤害感受器 被证明可以在过敏和细菌感染中调节肺部免疫细胞，但人们对此知之甚少 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起着 通过与免疫细胞的相互作用，特别是在促进肺癌发展中发挥关键作用 肿瘤相关的 IL-17+T 细胞和中性粒细胞。因此，针对伤害性神经 途径可以通过重新编程肿瘤来改善癌症对免疫治疗的反应 免疫微环境。实验上，我们将结合基因工程小鼠 采用尖端方法忠实再现人类肺腺癌的模型 细胞免疫学、癌症遗传学和神经元回路的功能操作。 具体来说，我们建议通过（1）建立肿瘤的作用来检验我们的中心假设 肺癌中感觉神经元的神经支配，（2）阐明肿瘤的机制 神经支配塑造癌症相关的免疫反应，(3) 决定临床前 结合基于检查点的伤害性神经通路的功效 免疫疗法。 我们的研究将为新兴但知之甚少的功能和 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 这里生成的结果将为未来神经免疫相互作用的研究奠定基础 在其他癌症类型中，揭示感觉神经通路和神经免疫 串扰可以作为癌症预防和治疗的新治疗靶点。