Investigating the neutrophil-sensory neuron crosstalk in lung cancer

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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.