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

项目总结/摘要 胰腺导管腺癌（PDAC）现在是美国癌症相关死亡的第三大原因 美国的绝大多数患者接受全身化疗作为新辅助治疗的一部分， 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患者其原因尚不清楚，并且考虑到目前还没有有希望的新药物， 目前，迫切需要新的策略来提高治疗反应性或确定预防措施， needed.我们的小组和其他人已经报道了宿主微生物组对PDAC发育的重要性， 进展微生物组是共享每个个体的身体空间的微生物的环境， 越来越多地与包括胰腺癌在内的各种人类疾病相关。基础上 之前发表的工作和我们实验室的挑衅性初步数据，我们提出了新的实验， 鉴定作为NK细胞调节剂的细菌及其抗肿瘤功能， 化疗，并提供预防和治疗策略。我们的创新方法利用gnotobiotic 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迟或阻止PDAC的发展， 此外，增强常用化疗药物吉西他滨和5-FU的抗肿瘤功效， 治疗PDAC为了检验这一假设，我们提出以下具体目标： 目的1：建立E.利用异种移植物和遗传学阻断来防止PDAC发展 胰腺癌的小鼠模型。 目标2：确定E.在PDAC患者中，阻断以增强化疗疗效。 随着特定目的的实现，该提案将确认肠球菌的作用，以提高 NK细胞在PDAC预防中的抗PDAC作用及其对化疗治疗的反应。等 知识将促进我们对影响PDAC反应性的宿主因素的理解， 化疗，并提供变革性的数据，以支持美国国立卫生研究院R 01应用程序， 第一次在人体试验的细菌操纵与E。靶向NK细胞的抗PDAC作用的抑制剂， 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.