Impact of the Microbiome on the Efficacy of Radiation Therapy

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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.