Pro-tumor functions of neutrophils in squamous cell lung cancer

项目摘要 鳞状细胞肺癌是非小细胞肺癌(NSCLC)的一个亚型，是第二常见的类型 患上了肺癌。也被称为肺鳞状细胞癌(SCC)，SCC负责大约85,000个新的 每年有肺癌病例，仅在美国就有约50,000人死亡。SCC与其他SCC不同 非小细胞肺癌(腺癌)的主要亚型：组织学、生物标记物表达、基因组改变、 免疫微环境与治疗反应。鳞状细胞癌的治疗选择有限，仅限于 化疗和最近的免疫疗法，这只对一小部分患者有效。一个重大的未满足的问题 治疗鳞癌的需要是确定新的治疗靶点和治疗策略来对抗 这种病。鳞状细胞癌具有独特的组织病理学和富含促结缔组织的复杂微环境。 间质、角质化和免疫细胞。具体地说，肿瘤相关的中性粒细胞(TAN)在 小鼠和人鳞状细胞癌和中性粒细胞的丰度与预后差和对 免疫疗法。关于TANS如何影响SCC肿瘤进展和治疗，我们知之甚少。 回应。众所周知，在缺乏三维结构的细胞培养中建立SCC模型是非常困难的 肿瘤、完整的免疫系统和血管系统。基因工程小鼠模型(GEMM)提供 一个可以高度概括人类疾病的复杂生命系统。我们的实验室首创了 开发首个SOX2驱动的SCC GEMM。我们最近开发了一种快速的新的GEMM，基于 Sox2/Lkb1/Nkx2-1(SNL)的改变，其中SCC肿瘤在以下方面与人类疾病高度相似 组织病理学、遗传学和免疫微环境。这种新的SNL模式代表了一种独特的免疫- 研究晒黑皮肤如何影响肿瘤进展和治疗反应的有效工具。的目标是 本研究旨在阐明TANS在肺鳞癌发生、发展和应答中的作用。 心理治疗。我们假设，棕褐色通过增加活性氧(ROS)来促进鳞状细胞的命运， 它们与肿瘤转分化有关，并通过促进中性粒细胞胞外陷阱(NETsis)而发挥作用。至 检验这些假说，我们将：1)确定TANS改变肿瘤细胞命运的机制。2)确定 TANs是否通过ROS和/或NETase促进鳞状肺癌的进展。3)确定是否 中性粒细胞减少可增强对化疗和/或免疫治疗的反应。这种方法是创新的。 因为我们将采用：1)我们的新型免疫活性SCC GEMM，它概括了 人类疾病，2)正在进行临床试验的中性粒细胞去除策略，3)最先进的技术 包括单细胞RNA测序和天然抗癌药物。这项研究是 意义重大，因为SCC中的Tan函数几乎完全没有被研究过，而Tan可能代表着一种新的 这种难治性疾病的治疗目标。

Project Summary Squamous cell lung cancer, a subtype of non-small cell lung cancer (NSCLC), is the second most common type of lung cancer. Also known as squamous cell carcinoma (SCC) of the lung, SCC is responsible for ~85,000 new cases of lung cancer each year and ~50,000 deaths in the United States alone. SCC is distinct from the other major subtype of NSCLC (adenocarcinoma) in terms of its histology, biomarker expression, genomic alterations, immune microenvironment and response to therapy. SCC has limited therapeutic options that are confined to chemotherapy and more recently, immunotherapy, which is only effective in a subset of patients. A major unmet need for the treatment of SCC is the identification of new therapeutic targets and treatment strategies to combat this disease. SCC has a unique histopathology and a complex microenvironment that is rich with desmoplastic stroma, keratinization and immune cells. Specifically, tumor-associated neutrophils (TANs) are enriched in mouse and human SCC, and neutrophil abundance correlates with poor prognosis and poor response to immunotherapy. Relatively little is known about how TANs impact SCC tumor progression and therapeutic response. It is notoriously difficult to model SCC in cell culture, which lacks the three-dimensional architecture of tumors, an intact immune system, and vasculature. Genetically-engineered mouse models (GEMMs) provide a complex living system that can highly recapitulate the human disease. Our laboratory pioneered the development of the first SOX2-driven SCC GEMM. We recently developed a rapid new GEMM based on alterations in Sox2/Lkb1/Nkx2-1 (SNL) where SCC tumors highly resemble the human disease in terms of histopathology, genetics, and immune microenvironment. This new SNL model represents a unique immune- competent tool to investigate how TANs shape tumor progression and therapeutic response. The objective of this study is to elucidate the role of TANs in squamous lung cancer development, progression and response to therapy. We hypothesize that TANs promote squamous cell fate by increasing reactive oxygen species (ROS), which are implicated in tumor transdifferentiation, and by promoting neutrophil extracellular traps (NETosis). To test these hypotheses, we will: 1) Determine the mechanism by which TANs alter tumor cell fate. 2) Determine whether TANs promote squamous lung cancer progression via ROS and/or NETosis. 3) Determine whether neutrophil depletion enhances response to chemotherapy and/or immunotherapy. This approach is innovative because we will employ: 1) our novel immune-competent SCC GEMM that recapitulates key features of the human disease, 2) neutrophil depletion strategies that are in clinical trials, and 3) state-of-the-art technologies including single cell RNA-sequencing and natural cancer-associated inhibitors of NETosis. This research is significant because TAN function in SCC is almost completely unexplored and TANs may represent a new therapeutic target for this intractable disease.