Radiotherapy (RT) is an established pillar of oncology employed to treat nearly half of all cancer patients at some stage of their therapy. While the role of the immune system in mediating both improved local responses, as well as the rarely observed systemic responses to radiation has been appreciated for decades, the underlying mechanisms governing the efficiency of immune mobilization in this context remain poorly defined. We recently showed that the response to radiation-induced DNA damage in cancer cells triggers upregulation of anti-phagocytosis checkpoints, which act to prevent tumor antigen cross-presentation and downstream activation of T cells which could otherwise mediate systemic...

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Radiotherapy (RT) is an established pillar of oncology employed to treat nearly half of all cancer patients at some stage of their therapy. While the role of the immune system in mediating both improved local responses, as well as the rarely observed systemic responses to radiation has been appreciated for decades, the underlying mechanisms governing the efficiency of immune mobilization in this context remain poorly defined. We recently showed that the response to radiation-induced DNA damage in cancer cells triggers upregulation of anti-phagocytosis checkpoints, which act to prevent tumor antigen cross-presentation and downstream activation of T cells which could otherwise mediate systemic anti-tumor immune responses. The relationship between various DNA damage response elements and control of specific "don't eat me" signals on dying tumor cells post-RT remains unknown; however, as does the impact of blocking these elements on cellular DNA integrity, mechanism of cell death, and induction of pro-phagocytic "eat me" signals. When irradiated tumor cells die and are readily phagocytosed by myeloid cells that, in turn, activate and cross-present antigen to T cells, complete immune-mediate regression of both targeted and non-irradiated "abscopal" lesions can be achieved. Our proposal will explore the hypothesis that disruption of critical elements of the DNA Damage Response (DDR) pathway can prevent induction of anti-phagocytosis checkpoint ligands following RT, thereby fostering efficient tumor antigen cross-presentation and generation of potentially sterilizing systemic anti-tumor immunity. In models of lung and colorectal cancer, we will explore how each DNA repair process triggered by RT acts to limit tumor immunogenicity, as well as how blocking key elements of these processes can improve post-RT anti-tumor immunity and act with other immunotherapies to promote systemic cancer regression.

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