Microbiota-mediated enhancement of the anti-tumor effect of natural killer cells

项目摘要/摘要 胰腺导管腺癌(PDAC)是当今世界上与癌症相关的第三大死亡原因。 美国。绝大多数患者接受全身化疗作为新辅助剂的一部分， 辅助，或姑息治疗方案。这些全身性药物不能提供持久的生存益处。 PDAC患者。原因尚不清楚，而且考虑到在 地平线，提高治疗响应性或确定预防措施的新战略迫切需要 需要的。我们的团队和其他人已经报告了宿主微生物组在PDAC发育和 进步。微生物群是微生物的环境，它们共享每个个体的身体空间和 越来越多地与各种人类疾病有关，包括胰腺癌。在基础上建设 之前发表的工作和来自我们实验室的具有挑衅性的初步数据，我们提出了新的实验，将 鉴定细菌作为NK细胞的调节剂及其抗肿瘤功能，以增强对 并提供预防和治疗策略。我们利用诺生素的创新方法 技术、微生物操作和先天免疫系统，以增强PDAC对 以前没有进行过化疗，这将推动胰腺癌研究领域的发展。 我们假设选择性肠道细菌可以延缓或阻止PDAC的发展和 此外，增强常用化疗药物吉西他滨和5-FU的抗肿瘤效果 治疗PDAC。为了检验这一假设，我们提出了以下具体目标： 目的1：利用异种移植和基因治疗，建立平野沙门氏菌阻止PDAC发展的能力。 小鼠胰腺癌模型。 目的2：建立平野艾美耳球虫对PDAC化疗疗效的影响。 随着具体目标的实现，这项建议将确认河野肠球菌的作用，以增强 NK细胞在PDAC预防中的抗PDAC作用及其对化疗的反应是这样的 知识将促进我们对影响PDAC响应能力的主机因素的理解 并提供变革性数据，以支持美国国立卫生研究院R01应用程序和 首次在人类试验中使用E.hirae进行细菌操纵，目标是NK细胞作为一种 预防和治疗策略。

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is now the 3rd leading cause of cancer related death in the United States. The overwhelming majority of patients receive systemic chemotherapy as part of a neoadjuvant, adjuvant, or palliative treatment regimen. These systemic agents do not provide durable survival benefits in patients with PDAC. The reason for this is unknown and given that there are no promising new agents on the horizon, novel strategies to increase treatment responsiveness or identify preventative measures are desperately needed. Our group and others have reported the importance of the host microbiome on PDAC development and progression. The microbiome is the milieu of microorganisms that share the body space of every individual and has been increasingly associated with a variety of human diseases, including pancreatic cancer. Building on prior published work and provocative preliminary data from our lab, we propose novel experiments that will identify bacteria as modulators of NK cells and their anti-tumor function in order to augment response to chemotherapy and provide a preventative and treatment strategy. Our innovative approach utilizing gnotobiotic technology, microbial manipulation, and the innate immune system to enhance PDAC responsiveness to chemotherapy has not been undertaken previously and will advance the field of pancreatic cancer research. We hypothesize that selective intestinal bacteria can delay or prevent PDAC development and furthermore, enhance the anti-tumor efficacy of gemcitabine and 5-FU, common chemotherapeutic agents used to treat PDAC. In order to test this hypothesis, we propose the following specific aims: Aim 1: Establish the ability of E. hirae to prevent PDAC development utilizing a xenograft and genetic mouse model of pancreatic cancer. Aim 2: Establish the impact of E. hirae to augment chemotherapy efficacy in PDAC. With fulfillment of the Specific Aims, this proposal will confirm the role of Enterococcus hirae to enhance the anti-PDAC role of NK cells in PDAC prevention as well as its response to chemotherapy treatment. Such knowledge will advance our understanding of host factors that impact the responsiveness of PDAC to chemotherapy and provide transformative data to support a National Institutes of Health R01 application and first-in-human trials for bacterial manipulation with E. hirae that targets the anti-PDAC role of NK cells as a preventative and treatment strategy.