Impact of the Microbiome on the Efficacy of Radiation Therapy

微生物组对放射治疗疗效的影响

• 批准号: 10001011
• 负责人: Stephen L. Shiao
• 金额: $ 35万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001011
• 关键词: Ablation; Address; Affect; Animals; Antibiotic Therapy; Antibiotics; Antibodies; Antifungal Agents; Aspergillus; Asthma; Bacteria; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cancer Etiology; Candida tropicalis; Cessation of life; Chemotherapy and/or radiation; Chronic; Communities; Cyclophosphamide; DNA Damage; Data; Dendritic Cells; Development; Diagnosis; Disease; Dose; Ecosystem; Effectiveness; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Fostering; Genetic; Immune; Immune response; Immune system; Immunohistochemistry; Immunosuppression; Inflammation; Inflammatory Response; Interferon Type II; Interleukin-4; Intestines; Ionizing radiation; Kinetics; Lead; Malignant Neoplasms; Mediating; Mus; Nature; North America; Organism; Pathway interactions; Patients; Play; Population; Radiation; Radiation therapy; Regulation; Research; Research Proposals; Role; Saccharomyces cerevisiae; Schedule; Shapes; Solid Neoplasm; T-Lymphocyte; Testing; Therapeutic; Tumor Immunity; Tumor-infiltrating immune cells; Woman; Work; anti-cancer; anti-tumor immune response; bacteriome; base; chemotherapy; commensal bacteria; dysbiosis; fungal microbiota; fungus; gut bacteria; gut microbiota; immunogenic cell death; in vivo; insight; irradiation; macrophage; malignant breast neoplasm; microbiome; mouse model; mycobiome; neoplastic cell; novel; oxaliplatin; programs; radiation effect; radiation response; response; tumor; tumor growth

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.

项目总结 乳腺癌仍然是北美最常见的癌症，是癌症死亡的第二大原因 在女人身上。放射治疗(RT)在乳腺癌的治疗中发挥着不可或缺的作用，超过一半的患者 所有乳腺癌患者在治疗过程中都会接受放射治疗。传统的 放射治疗的观点主要集中在放射治疗对肿瘤细胞本身的影响。然而，最近的研究表明 证明了免疫系统在决定肿瘤对RT的反应中起着关键作用。此外，还有多个 研究已经确定细菌和真菌微生物群是系统免疫反应的关键调节因素。 处于不同的炎症状态，包括化疗后免疫原性细胞死亡和哮喘 分别进行了分析。微生物群由数以万亿计的有机体和许多不同的物种组成，这些物种可以 支持或抑制正在进行的免疫反应，我们的初步数据表明，靶向 肠道细菌降低了RT的疗效，而靶向肠道真菌可以增强RT的疗效。这个 本研究建议的目的是探讨肠道细菌和真菌形成的机制(S) 对RT的反应。这项提议检验了细菌和真菌的组成 微生物组调节RT诱导的免疫反应，体内RT的有效性可以通过以下方式增强 以真菌微生物群为目标的特定物种。为了评估这一假设，以下目标是 建议：目的1：表征抗生素或抗真菌所致的肠道菌群失调对疗效的影响 目标2：确定细菌和真菌微生物区系的免疫机制(S) 调节肿瘤对RT的反应；以及目标3：检查特定肠道真菌在调节肿瘤对RT的反应中的作用 放射治疗的疗效。我们将使用先进的小动物照射器提供的焦点RT来实现这些目标 在小鼠乳腺癌模型中，研究RT在细菌或真菌失调环境中的作用 采用流式细胞术、免疫组织化学、定量聚合酶链式反应和酶联免疫吸附试验相结合的方法检测 肿瘤免疫状况的变化。我们还将确定特定真菌物种在调节 RT介导的抗肿瘤免疫反应。这项研究的意义在于，它将提供 肿瘤对辐射的免疫反应，这可能导致基于微生物组的新疗法的治疗 在乳腺癌和多种其他实体肿瘤中，RT在其中发挥着不可或缺的治疗作用。