Impact of the Microbiome on the Efficacy of Radiation Therapy

项目摘要 乳腺癌仍然是北美最常见的癌症，也是癌症死亡的第二大原因 在女人身上。放射治疗（RT）在乳腺癌的治疗中起着不可或缺的作用， 所有乳腺癌患者在治疗过程中接受放射治疗。常规 关于RT的观点主要集中在RT对肿瘤细胞本身的影响上。但最近的研究 证明了免疫系统在决定肿瘤对RT的反应中的关键作用。 研究已经确定细菌和真菌微生物群是全身免疫反应的关键调节剂 在各种炎症状态中，包括化疗后免疫原性细胞死亡和哮喘 分别微生物组由数万亿种生物和多种不同的物种组成， 支持或抑制正在进行的免疫反应，我们的初步数据表明， 肠道细菌降低RT的功效，而靶向肠道真菌可以增强RT的功效。 这项研究计划的目的是解决肠道细菌和真菌形成的机制 对RT的反应。该提案测试了细菌和真菌的组成 微生物组调节RT诱导的免疫应答，RT的功效可以通过以下方式在体内增强： 针对特定物种的真菌微生物组。为了评估这一假设，以下目标是 提出：目的1：表征抗生素或抗真菌药诱导的肠道生态失调对疗效的影响 目的2：确定细菌和真菌微生物群的免疫机制 调节肿瘤对RT的反应;目的3：检查特定肠道真菌在调节肿瘤对RT的反应中的作用。 我们将使用先进的小动物辐照器提供的局灶性RT来实现这些目标 在小鼠乳腺癌模型中，研究RT在细菌或真菌生态失调环境中的作用 使用流式细胞术、免疫组织化学、定量PCR和ELISA的组合来确定 肿瘤免疫特征的变化。我们还将确定特定真菌物种在介导 RT介导的抗肿瘤免疫应答。这项研究的意义在于它将为我们提供 研究肿瘤对辐射的免疫反应，这可能会导致新的基于微生物群的治疗方法。 乳腺癌和多种其他实体瘤，其中RT发挥着不可或缺的治疗作用。

PROJECT SUMMARY Breast cancer remains the most common cancer in North America and the second leading cause of cancer death in women. Radiation therapy (RT) plays an integral part in the treatment of breast cancer with more than half of all breast cancer patients receiving radiation sometime during the course of their treatment. The conventional view of RT has largely focused on the effect of RT on the tumor cells themselves. However, recent studies have demonstrated a critical role for the immune system in determining the response of tumors to RT. Further, multiple studies have identified the bacterial and fungal microbiomes as key regulators of systemic immune responses in various in states of inflammation including post-chemotherapy immunogenic cell death and asthma respectively. The microbiome consists of trillions of organisms and a multitude of different species that can either support or suppress an ongoing immune response and our preliminary data suggests that targeting intestinal bacteria reduces the efficacy of RT whereas targeting gut fungi can enhance the efficacy of RT. The objective of this research proposal is to address the mechanism(s) by which intestinal bacteria and fungi shape the response to RT. The proposal tests the hypothesis that the composition of the bacterial and fungal microbiome regulates RT-induced immune responses and that the efficacy of RT can be enhanced in vivo by targeting specific species with the fungal microbiome. To evaluate this hypothesis, the following Aims are proposed: Aim 1: Characterize the effect of antibiotic- or antifungal-induced intestinal dysbiosis on the efficacy of radiation and chemotherapy; Aim 2: Define immune mechanism(s) of bacterial and fungal microbiota regulation of tumor responses to RT; and Aim 3: Examine the role of specific intestinal fungi in modulating the efficacy of RT. We will accomplish these aims using focal RT delivered with an advanced small animal irradiator in a murine model of breast cancer and studying the effects of RT in the setting of bacterial or fungal dysbiosis using a combination of flow cytometry, immunohistochemistry, quantitative PCR and ELISA to determine the changes in the immune profile of tumors. We will also determine the role of specific fungal species in mediating the RT-mediated anti-tumor immune response. The significance of this research is that it will provide insights into the tumor immune responses to radiation that may lead to new microbiome-based therapies for the treatment of breast cancer and the multiple other solid tumors in which RT plays an integral therapeutic role.