Grant: Travel Awards - Institute Community Support

When microbes enter the body, foreign DNA is carried into cells and activates sensors termed pattern recognition receptors, or PRRs. This leads to activation of the immune system and elimination of the infection. In tumor cells, unstable tumor DNA and high levels of DNA damage lead to DNA leaking into improper cell compartments, also resulting in PRR activation. This effect is further increased by treatments like radiation or chemotherapy. Activation of anti-tumor immunity in this manner has been identified in previous studies as a key mechanism for tumor clearance by these treatments. However, it is not fully understood how the leaked DNA changes between different subtypes of cancer and with treatment regimen. To investigate this, we propose to collect leaked DNA from colorectal cancer cells of different types and following radiation or 5-fluorouracil treatment. We will then use this DNA to stimulate immune cells and see if some types result in more or less activation of PRRs in immune cells. Our data suggests leaked DNA from certain cancer subtypes induces stronger activation of the immune system. Radiation and 5-fluorouracil treatments also increase this activation capacity. Additionally, we aim to identify the specific differences within the leaked DNA that may explain these trends. Screening has identified repeats present in the most highly immune activating DNAs, and we observe that these repeats induce increased immune cell activation and anti-tumor immunity. Knowing what causes some DNA to be more stimulatory than others will allow for design of future immune activating therapies based on the most immune activating DNA sequences. As immune recognition of the tumor is crucial to treatment efficacy, this study will also increase our understanding of the relationship between genetic damage and anti-tumor immune activation, leading to improved treatment choice decisions.