(Thursday, 8/2/2018) 1:00 PM - 3:00 PM
Room: Karl Dean Ballroom A1
Purpose: Recent study has detailed the role of the STING pathway (STimulator of INterferon Genes) as a mechanism of abscopal effects in radiation therapy, where radiation damage results in accumulation of cytosolic double-stranded DNA (dsDNA), upregulation of IFNB, and downstream priming of CD8+ T-cells. However, high doses can promote release of exonuclease Trex1, which degrades dsDNA and suppresses STING. This work explores the doses required to induce STING without suppression from Trex1 across a range of treatment modalities and oxygenation conditions.
Methods: Reference data on dsDNA content and Trex1 upregulation as a function of dose was taken from Vanpouille-Box (2017) assuming MC38 murine colon cancer cells, 225kVp radiation quality, and standard 20mmHg oxygen saturation. Monte Carlo Damage Simulation (MCDS) software was used to determine the quantity of nucleic DNA DSB induced in a single-cell geometry at the referenced doses. Trex1 and dsDNA concentration were fitted as a function of DSB and applied to test conditions, assuming that equivalent DNA damage yields equivalent downstream effects. New damage simulations were performed with 225 kVp photons, 6MV photons, 5MeV protons, and 100 MeV protons for doses up to 30 Gy, varying intracellular oxygenation from 0-20mmHg. For each scenario, we found the dose required for maximum dsDNA buildup and the standard deviation of doses for high dsDNA.
Results: As oxygenation decreases, photon doses for peak dsDNA increase from 9 Gy at normoxia up to 23 Gy at anoxia. Lower rates of dsDNA accumulation result in a wider dose window for STING and delayed onset of Trex1 suppression. Higher LET radiation causes faster buildup of dsDNA and Trex1.
Conclusion: STING is a promising mechanism to generate an anti-tumor immunogenic response to radiation, and here we demonstrate a relation between STING promoters and suppressors, dose, LET, and oxygen saturation. This work will be experimentally validated in-vitro.
Keywords
Not Applicable / None Entered.
Taxonomy
TH- Radiobiology(RBio)/Biology(Bio): RBio- general
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