This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-21-100. Elucidating B cell-mediated mechanisms of response and resistance to radiation therapy in soft tissue sarcoma Project Summary/Abstract Soft tissue sarcoma is a lethal mesenchymal cancer. Radiation therapy remains a cornerstone of treatment, but the immunologic basis of response and resistance to radiation therapy remains poorly understood. Historically, research on radiation treatment has largely focused on methodological issues of its delivery (e.g., optimizing dose and fractionation) and the effects of ionizing radiation on tumor cells, with less focus on the impact of radiation on the intratumoral and systemic immune response. Presumptive immune-mediated consequences of radiation—such as the abscopal effect and higher incidence of surgical wound infection after radiation—are well documented in the clinic, but the mechanistic basis of these phenomena are not understood. Here we propose to longitudinally characterize the human immune response to radiation (e.g. baseline, on-treatment, post-treatment) in sarcoma patients and further investigate these findings in animal models of sarcoma. We are particularly interested in the humoral immune response because emerging data show a strong association between B cells and high antibody titers with response to immunotherapy and survival in sarcoma patients. We will provide a comprehensive view of the complex humoral response to radiation treatment by using a variety of genomic-based, biochemical, and functional assays to gain insight into the developmental history, phenotype, and function of intratumoral and circulating B cell populations. This will potentially inform the design of humoral-based therapies that can be used in combination with radiation treatment for sarcoma patients.