Dissecting Mechanisms of Immune Mediated Radiation Resistance in Sarcomas

Soft tissue sarcomas represent a rare, aggressive, and complex group of malignancies. Patients with large or high-grade soft tissue sarcomas often receive radiation therapy in combination with surgery. Some sarcomas may occur at an anatomic site where surgery is not feasible. In these patients, the sarcomas are treated with definitive radiotherapy with or without chemotherapy. Unfortunately, many sarcomas are resistant to radiation, but the mechanisms of radiation resistance are not well understood. Based on our preliminary preclinical data, we hypothesize that specific myeloid cell populations within the immune system drive radiation resistance in soft tissue sarcomas, which can decrease tumor growth delay after radiation therapy and may prevent long term tumor cure. We will utilize a mouse model in which primary soft tissue sarcomas develop in a native microenvironment to define the role of myeloid cells in the sarcoma response to radiation therapy. Using a mouse model of primary soft tissue sarcoma, we will genetically and pharmacologically manipulate myeloid cell populations to determine whether they confer resistance to radiation-induced tumor growth delay and prevent permanent tumor regression after radiation therapy. By understanding the interplay between the immune system and tumor response to radiation therapy, we seek to identify potential targets that influence radiation efficacy and can be modulated to improve local tumor control by radiation therapy.