Investigating the neutrophil-sensory neuron crosstalk in lung cancer

许多类型的实体肿瘤由神经系统的不同分支支配，就像 免疫系统，感知并对内部和环境刺激做出反应。然而，神经 长期以来一直被视为癌症领域的被动旁观者。人们对此知之甚少 系统调节肿瘤相关免疫反应，以及哪些因子在组织中具有特异性 微环境塑造肿瘤神经支配。因此，我们研究的首要目标是 深入而广泛地了解癌症中的神经免疫相互作用，重点 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更有效地治疗癌症。 特别有趣的是，肺神经伤害性感受器是一种特殊的感觉神经元，控制着 咳嗽和疼痛是肺癌患者最常见的临床症状。而伤害性感受器 被证明在过敏和细菌感染中调节肺免疫细胞，但对此知之甚少 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在 通过与免疫细胞的交叉对话促进肺癌发展的关键作用，尤其是 肿瘤相关IL-17+T细胞和中性粒细胞。因此，针对伤害性神经 通路可以通过对肿瘤重新编程来提高对免疫治疗的癌症反应 免疫微环境。在实验上，我们将结合基因工程小鼠 用尖端方法逼真复制人肺腺癌的模型 在细胞免疫学、癌症遗传学和神经元回路的功能操作方面。 具体地说，我们建议通过(1)确定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)阐明肿瘤的发病机制 神经支配塑造癌症相关免疫反应，(3)决定临床前 联合检查点定位伤害性神经通路的疗效观察 免疫疗法。 我们的研究将为新出现但鲜为人知的功能和 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 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，揭示了感觉神经通路和神经免疫 串扰可作为癌症预防和治疗的新治疗靶点。

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.