A blueprint for neutrophil heterogeneity and reprogramming in cancer

项目概要金成成博士 中性粒细胞是人体血液中最丰富的免疫细胞。它们是多功能的先天性骨髓细胞 在病原体感染、组织修复以及癌症中发挥关键作用。作为肿瘤的主要成分- 在多种癌症类型中，中性粒细胞已经成为促进免疫细胞的关键角色。 癌症通过多种机制进展，例如介导组织重塑，驱动局部炎症， 抑制抗肿瘤T细胞。然而，目前没有可行的策略可用于针对癌症的中性粒细胞 疗法这揭示了一些基本的问题和挑战：肿瘤相关中性粒细胞（TAN） 正常血液中性粒细胞吗TME中的所有中性粒细胞是否功能相同，并执行广泛的 一系列的肿瘤促进活动？有没有可能选择性地靶向促肿瘤的中性粒细胞， 损害了那些保护我们免受细菌感染的关键因素？ 我们的愿景是发展一个深入和广泛的理解转录和表观遗传重编程 肿瘤微环境（TME）中的中性粒细胞。这将揭示新的调控机制， 肿瘤促进中性粒细胞，可作为精确癌症免疫治疗的靶点，同时保留 健康组织中的免疫监视。我们的战略是采取一种综合方法， 我们在基因工程小鼠模型中建立的专业知识和知识。具体来说，我们将 (1)联合收割机在不同TME中对中性粒细胞进行单细胞表型、转录和染色质分析 水平，（2）应用命运作图和空间转录组学揭示TME中中性粒细胞的动态，（3）建立 并利用新的遗传扰动工具来鉴定和功能验证中性粒细胞的关键调节因子， 在癌症中的作用 通过分析来自不同微环境的组织/肿瘤相关中性粒细胞，我们已经鉴定出不同的肿瘤相关中性粒细胞。 中性粒细胞亚群由TME的不同组分诱导。因此，我们的总体假设是 肿瘤微环境中的特定因素，如局部微生物群和组织驻留免疫细胞， 以及癌细胞的遗传组成和免疫原性可能差异性地调节嗜中性粒细胞。 我们的目标是从TME中识别出细胞外源性因子，这些因子可将中性粒细胞重编程为功能上离散的 子集与此同时，我们将应用新技术来跟踪TAN，并剖析嗜中性粒细胞的内在通路， 指导它们在癌症中的功能多样化。 我们的研究将为癌症中中性粒细胞反应的转录控制提供蓝图， 癌症中中性粒细胞功能的阶段/基因/环境特异性治疗调节的可能性。 此外，这里产生的概念和技术进步将为未来的发展奠定基础。 研究其他癌症类型及其他类型的中性粒细胞，揭示通路和分子 可以作为新的治疗靶点来操纵中性粒细胞以治疗癌症和其他疾病。

Project Summary Chengcheng Jin, Ph.D Neutrophils are the most abundant immune cells in human blood. They are multi-functional innate myeloid cells that play key roles in pathogen infection, tissue repair, as well as cancer. As a main composition of the tumor- associated immune cells in multiple cancer types, neutrophils have emerged as a critical player to promote cancer progression via diverse mechanisms, such as mediating tissue remodeling, driving local inflammation, suppressing anti-tumor T cells. However, no viable strategy is currently available to target neutrophils for cancer therapy. This reveals fundamental questions and challenges: are tumor-associated neutrophils (TAN) distinct from normal blood neutrophils? Do all the neutrophils in the TME function identically and carry out the broad range of tumor-promoting activities? Is it possible to selectively target the tumor-promoting neutrophils without impairing those essential for protecting us from bacterial infection? Our vision is to develop an in-depth and broad understanding of transcriptional and epigenetic reprogramming of neutrophils in the tumor microenvironment (TME). This will reveal novel regulatory mechanisms unique to tumor-promoting neutrophils that can serve as targets of precision cancer immunotherapies while preserving immune surveillance in healthy tissues. Our strategy is to take an integrated approach that leverages the unique expertise and knowledge that we have established in genetically engineered mouse models. Specifically, we will (1) combine phenotypic, transcriptional and chromatin profiling of neutrophils in different TME at the single-cell level, (2) apply fate mapping and spatial transcriptomics to reveal the neutrophil dynamics in TME, (3) establish and utilize novel genetic perturbation tools to identify and functionally validate key regulators of neutrophil function in cancer. By analyzing the tissue/tumor-associated neutrophils from different microenvironment, we have identified distinct neutrophil subsets that are induced by different components of the TME. Therefore, our overall hypothesis is that specific factors in the tumor microenvironment such as the local microbiota and tissue-resident immune cells, as well as the genetic makeup and immunogenicity of cancer cells may differentially regulate the neutrophils. Our goal is to identify cell-extrinsic factors from the TME that reprogram neutrophils to functionally discrete subsets. Meanwhile, we will apply novel techniques to track TANs and dissect neutrophil-intrinsic pathways that direct their functional diversification in cancer. Our study will provide a blueprint for transcriptional control of neutrophil responses in cancer and opens possibilities for stage/gene/environment-specific therapeutic modulation of neutrophil function in cancer. Furthermore, the conceptual and technological advances generated here will build the foundation for future investigations into neutrophils in additional cancer types and beyond, shedding light on pathways and molecules that can serve as novel therapeutic targets to manipulate neutrophils for treating cancer and other diseases.