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: 10241486
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241486
• 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

项目成果

Effects of Radiation on the Tumor Microenvironment.

• DOI: 10.1016/j.semradonc.2019.12.004
• 发表时间: 2020-04
• 期刊: Seminars in radiation oncology
• 影响因子: 3.5
• 作者: Monjazeb AM;Schalper KA;Villarroel-Espindola F;Nguyen A;Shiao SL;Young K
• 通讯作者: Young K

Commensal bacteria and fungi differentially regulate tumor responses to radiation therapy.

共生细菌和真菌差异调节肿瘤对放射治疗的反应。

• DOI: 10.1016/j.ccell.2021.07.002
• 发表时间: 2021-09-13
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Shiao SL;Kershaw KM;Limon JJ;You S;Yoon J;Ko EY;Guarnerio J;Potdar AA;McGovern DPB;Bose S;Dar TB;Noe P;Lee J;Kubota Y;Maymi VI;Davis MJ;Henson RM;Choi RY;Yang W;Tang J;Gargus M;Prince AD;Zumsteg ZS;Underhill DM
• 通讯作者: Underhill DM

Natural killer cell activity and prostate cancer risk in veteran men undergoing prostate biopsy.

• DOI: 10.1016/j.canep.2019.101578
• 发表时间: 2019-10
• 期刊: Cancer epidemiology
• 影响因子: 2.6
• 作者: Vidal AC;Howard LE;Wiggins E;De Hoedt AM;Shiao SL;Knott S;Taioli E;Fowke JH;Freedland SJ
• 通讯作者: Freedland SJ

Advances in Combining Radiation and Immunotherapy in Breast Cancer.

• DOI: 10.1016/j.clbc.2021.03.007
• 发表时间: 2021-04
• 期刊: Clinical breast cancer
• 影响因子: 3.1
• 作者: Nguyen AT;Shiao SL;McArthur HL
• 通讯作者: McArthur HL

The role of macrophage phenotype in regulating the response to radiation therapy.

• DOI: 10.1016/j.trsl.2017.11.002
• 发表时间: 2018-01
• 期刊: Translational research : the journal of laboratory and clinical medicine
• 作者: Shi X;Shiao SL
• 通讯作者: Shiao SL