A blueprint for neutrophil heterogeneity and reprogramming in cancer

项目总结金成城博士 中性粒细胞是人类血液中含量最丰富的免疫细胞。它们是多功能的先天髓系细胞。 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- 相关免疫细胞在多种癌症类型中，中性粒细胞已成为促进 癌症的进展通过不同的机制，如介导组织重塑，推动局部炎症， 抑制抗肿瘤T细胞。然而，目前还没有可行的策略来针对癌症的中性粒细胞。 心理治疗。这揭示了根本的问题和挑战：肿瘤相关的中性粒细胞(TAN)与 来自正常血液中的中性粒细胞？TME中的所有中性粒细胞功能是否相同，并进行广泛的 一系列促进肿瘤的活动？有没有可能选择性地靶向促进肿瘤的中性粒细胞而不需要 损害那些保护我们免受细菌感染所必需的物质吗？ 我们的愿景是发展对转录和表观遗传重新编程的深入和广泛的理解 肿瘤微环境(TME)中性粒细胞的数量。这将揭示独特的新的监管机制 促进肿瘤的中性粒细胞可作为精确癌症免疫治疗的靶点，同时保存 健康组织中的免疫监测。我们的战略是采取综合方法，利用独特的 我们在基因工程小鼠模型中建立的专业知识。具体来说，我们将 (1)在单细胞中结合不同TME中中性粒细胞的表型、转录和染色质图谱 水平，(2)应用Fate图谱和空间转录来揭示TME中性粒细胞的动态，(3)建立 并利用新的遗传扰动工具识别和功能验证中性粒细胞的关键调控因子 在癌症中起作用。 通过对来自不同微环境的组织/肿瘤相关中性粒细胞的分析，我们发现了不同的 由TME的不同成分诱导的中性粒细胞亚群。因此，我们的总体假设是 肿瘤微环境中的特定因素，如局部微生物区系和组织驻留免疫细胞， 此外，癌细胞的基因组成和免疫原性也可能对中性粒细胞进行不同的调节。 我们的目标是从TME中识别将中性粒细胞重新编程为功能离散的细胞外在因子 子集。同时，我们将应用新的技术来跟踪晒黑和解剖中性粒细胞的内在途径， 引导它们在癌症中的功能多样化。 我们的研究将为癌症中性粒细胞反应的转录控制提供蓝图，并打开 癌症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奠定基础 对中性粒细胞在其他癌症类型和其他癌症类型中的研究，揭示了途径和分子 这可以作为控制中性粒细胞治疗癌症和其他疾病的新的治疗靶点。

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.