Enhancing radiation therapy by targeting CCR8+ tregs in cancer 3209

Abstract Description Using the Kaede mouse model, we identified that 17.6% of the Tregs that have recently migrated from the photoconverted tumor-draining lymph node to the tumor following radiation therapy (RT) are CCR8+. We hypothesize that eliminating CCR8-expressing Tregs along with RT will enhance overall survival. In the MC38 tumor model combining RT (d14) and anti-CCR8 (d14,17,21) resulted in a median survival 76.5 versus 40 days for RT (p 0.0001) alone and 33 days for anti-CCR8 alone (p 0.0001). To identify optimal sequencing, we administered anti-CCR8 either before RT (‘pre’ d7,10,14) or after RT (‘post’ d17,20,24). The ‘pre’ strategy achieved a survival rate of 62.5% at day 175 and the ‘post’ strategy resulted in a median survival of 54.5 days. In the CT26 tumor model, we explored a dual flank model with one tumor treated with RT and the contralateral tumor left unirradiated in combination with anti-CCR8. The median survival for combination therapy was 105 versus 25 days for RT (p 0.0001) and 55.5 days for anti-CCR8 (p = 0.0448). Combination therapy cured 7/8 non-RT treated tumors, while RT alone resulted in no cures. We tested the combined strategy with the depletion of CD8, CD4, or NK cells and found no significant change in survival with CD4 or NK depletion. CD8 depletion resulted in a reduced median survival of 43.5 days (p = 0.0003). We propose trials developing anti-CCR8 therapy should look to incorporate combination radiation approaches in addition to single agent strategies. Funding Sources This research was funded by NCI R01CA182311, NCI R01CA244142, and R01CA208644, and by the Providence Foundation. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)