Rationale and Objective: Cancer immunotherapy has become an effective way of targeting tumors in patients that have a pre-existing immune response targeting their tumor, and immune checkpoint inhibitors such as anti-CTLA-4 and anti-PD-1 can be used to re-stimulate the immune response and eliminate the cancer. In the case of metastatic breast cancer, patients often suffer from tumors that have little or no infiltration of anti-tumor immune cells. Here, the first task at hand is to help the patient trigger a new immune response that is specifically targeting the tumor cells, making them responsive to immune checkpoint inhibitors. Radiation therapy (RT) directed to a single tumor site has been shown to induce systemic immune responses in preclinical mouse models as well as in patients with advanced cancer. Essentially, the RT converts the tumor into a "cancer vaccine." However, there are suppressive factors within each tumor that limit the effectiveness of the RT to induce immune responses. High levels of the danger signal ATP is produced within the tumor following RT, but it is rapidly converted to adenosine (ADO) locally in the tumor. ADO is highly suppressive to the cells that are responsible for initiating the anti-tumor immune responses, the dendritic cells (DCs). Thus, we hypothesized that targeting ADO generation in the tumor following RT or its effects on DC and other immune cells may enhance the activation of anti-tumor immune responses by RT. This hypothesis is supported by our preliminary data in mouse models of metastatic cancer.

Career Goals: Since I started working with cancer research, I have been intrigued by the interplay between emerging tumors and the host's immune system. In breast cancer, where the clinical success of emerging immunotherapies has been limited, I believe that we need to combine immunotherapy with alternative approaches in order to be able to treat and cure more patients. My long-term career goal is to evolve into an independent researcher and focus my research to develop novel strategies to potentiate anti-tumor immunity against breast cancer. Leading this project with the proposed research plan will constitute a challenge that will force me to develop my research as well as my collaborative skills. I will be given the opportunity to pursue an exciting novel approach to treat advanced and metastatic breast cancer using a combination of ADO-blockade and RT to potentiate the use of immune checkpoint inhibitors. With the development plan that we have laid out, I will have access to a uniquely stimulating and multidisciplinary research environment and excellent support from my mentor, who is one of the pioneers in the field of radiation-induced anti-tumor immunity. I will have every opportunity to successfully reach the goals of the proposed project and start my transition into becoming an independent breast cancer researcher.

Applicability and Impact: This project addresses the overarching challenges of revolutionizing treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective and eliminate the mortality associated with breast cancer. Standard cancer therapy including RT and immune checkpoint inhibitors are currently ineffective in targeting advanced breast cancer. Patients suffering from breast cancer with low immune cell infiltration require novel therapeutic approaches in order to initiate anti-tumor immune responses that, if successful, could eliminate all tumors and cure the patient. The present study will evaluate whether a combination of RT and immune checkpoint inhibitors can be facilitated by modulating the tumor microenvironment at the time of treatment. This novel approach is taken with the purpose of making breast cancer patients that are currently without viable treatment options to become responsive to immune checkpoint inhibitors. The proposed project is translational and with immune checkpoint inhibitors in breast cancer patients and ADO-inhibitors currently being tested in clinical trials our treatment approach is thought to be implemented in human medicinal practice within a short time frame. The project will contribute with essential knowledge about how ADO regulates the immune response following RT, and with our findings, we will lay a foundation for the implementation of ADO-blockade and RT as a means to induce anti-tumor immunity in breast cancer patients making them responsive to immune checkpoint blockade.