Role of Neutrophil Extracellular Traps in Pancreatic Cancer

项目总结/摘要-神经细胞外陷阱在胰腺癌中的作用 胰腺导管腺癌（PDAC）是一种破坏性的恶性肿瘤，其特征是纤维化和 免疫抑制性肿瘤微环境促进对治疗的抗性。的创新方法 克服PDAC肿瘤微环境（TME）中驱动治疗抗性的病理生理学， 迫切需要的。独特的纤维化TME充当物理屏障以防止T细胞浸润， 具有有限的功能性脉管系统，这减少了化疗的输送。我们最近 证实了中性粒细胞胞外陷阱（NET），其中活化的中性粒细胞释放其 细胞内内容物包括DNA、组蛋白和颗粒进入细胞外空间或循环， 在胰腺癌中上调，通过胰腺星状细胞驱动肿瘤生长并促进纤维化 (PSC)activation.蛋白质精氨酸脱亚胺酶4（PAD 4）是瓜氨酸化组蛋白以允许 解旋和从细胞中排出，是NET形成所必需的，提供了一种潜在的治疗方法， 在癌症中NET抑制的靶点。PAD 4-/-小鼠减少了局部和全身NET形成，导致 限制肿瘤生长并提高小鼠原位胰腺癌的存活率。我们已经生成 初步数据表明，具有PAD 4基因消除的PDAC小鼠具有增强的细胞毒性， 免疫反应和增加的功能性脉管系统。本申请的目的是确定 NET促进对免疫疗法的治疗抗性的有效机制， 化疗我们将探讨PAD 4消融对自发转基因Kras和p53的影响。 介导的PDAC。在目标1中，我们将用免疫组织化学方法彻底评估对PAD 4消融/抑制的免疫应答。 关注由于NET减少而导致的PSC活化的减少如何增强T细胞浸润， 功能，促进对免疫疗法的反应。在目标2中，我们将评估NET对 血管生成、功能性脉管系统和细胞毒性化疗的递送。这些研究将支持 新的治疗方法与标准治疗化疗相结合的转化， 免疫疗法，以最大限度地提高这种毁灭性疾病的治疗反应。

PROJECT SUMMARY/ABSTRACT – Role of Neutrophil Extracellular Traps in Pancreatic Cancer Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy characterized by a fibrotic and immunosuppressive tumor microenvironment that promotes resistance to therapy. Innovative approaches to overcome the pathophysiology in the PDAC tumor microenvironment (TME) that drive treatment resistance are desperately needed. The uniquely fibrotic TME serves as a physical barrier to prevent infiltration of T cells and has limited functional vasculature, which reduces the delivery of chemotherapy. We have recently demonstrated that neutrophil extracellular traps (NETs), in which activated neutrophils release their intracellular contents including DNA, histones and granules into the extracellular space or circulation, are upregulated in pancreatic cancer, driving tumor growth and promoting fibrosis through pancreatic stellate cell (PSC) activation. Protein arginine deiminase 4 (PAD4) is an enzyme that citrullinates histones to allow for unwinding and expulsion from the cell and is required for NET formation, providing a potential therapeutic target for NET inhibition in cancer. PAD4-/- mice have diminished local and systemic NET formation, resulting in limited tumor growth and improved survival in murine orthotopic pancreatic cancer. We have generated preliminary data demonstrating that PDAC mice with genetic ablation of PAD4 have enhanced cytotoxic immune response and increased functional vasculature. The objective of this application is to identify the impactful mechanisms through which NETs promote treatment resistance to immunotherapy and chemotherapy. We will explore the impact of PAD4 ablation on spontaneous transgenic Kras and p53 mediated PDAC. In Aim 1, we will thoroughly evaluate the immune response to PAD4 ablation/inhibition with a focus on how reduction in PSC activation as a result of diminished NETs enhances T cell infiltration and function, promoting response to immunotherapy. In Aim 2, we will evaluate the changes that NETs have on angiogenesis, functional vasculature and delivery of cytotoxic chemotherapy. These studies will support translation of novel therapeutic approaches in combination with standard of care chemotherapy and immunotherapy to maximize treatment response in this devastating disease.