Abstract: Immunotherapy has recently emerged as a promising new approach to cancer treatment. Durable anti-tumor responses have been achieved with immune checkpoint inhibitors (ICIs) such as anti-PD1 and anti-CTLA4. However, most cancer patients respond poorly to ICIs, including soft tissue sarcoma patients. An important research objective in improving therapy for soft tissue sarcoma patients is to understand pathways that are associated with resistance to ICIs. Downregulation of the antigen presentation pathway has been associated with resistance to ICIs in various cancers. Radiation therapy, on the other hand, has been shown to increase antigen presentation. Although it has been postulated that radiotherapy enhances therapeutic effects of ICIs through upregulation of MHC-I molecules, the regulatory pathway(s) for radiation-induced MHC-I upregulation remains poorly understood. To investigate the role of radiotherapy in modulating tumor antigen presentation, I will use genetically engineered mouse models of autochthonous soft tissue sarcomas to dissect the mechanisms responsible for modulating MHC-I expression after radiation. The long-term goal of this project is to elucidate the mechanisms by which radiotherapy can help to overcome immunotherapy resistance. The primary objective of this proposal is to investigate the underlying pathway through which radiotherapy modulates the MHC-I antigen presentation pathway. The central hypothesis of this study is that radiotherapy upregulates MHC-I expression in soft tissue sarcomas, which increases neoantigen presentation to the immune system and sensitizes tumor cells to cytotoxic T cell killings and ICI treatments. I will test this hypothesis in the following two specific aims: Aim 1: Investigate regulatory networks responsible for MHC-I expression in soft tissue sarcomas. Aim 2: Test whether radiation increases neoantigen presentation on tumor cells and antigen-presenting cells in vivo.