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RBE for STING Immunogenic Signaling From Low LET X-Rays and High LET Neutrons

D Miles1,2*, N Cao2, T Pulliam2, S Cherny2, R Stewart2, G Moffitt2, G Sandison2, P Nghiem2, P Goff2, E Hatch3, K Stantz1, (1) Purdue Univ, West Lafayette, IN, (2) University of Washington, Seattle, WA,(3) Fred Hutchinson Cancer Research Center


(Wednesday, 7/15/2020) 2:00 PM - 3:00 PM [Eastern Time (GMT-4)]

Room: Track 3

Purpose: Hypofractionated radiation can induce pro-immunogenic signals from cancer cells, by activating innate response mechanisms, such as Stimulator of Interferon Genes (STING), following DNA damage. High linear energy transfer (LET) radiation is predicted to be more immunogenic, inducing more, higher-complexity, DNA double strand breaks (DSBs) per unit dose compared to low-LET radiations. This work studies the in vitro dose-response characteristics of pro-and-anti-immunogenic signals from cancer cells subject to low-and-high-LET radiation.

Methods: Merkel cell carcinoma cells (MCC13) were irradiated using low-LET x-rays and high-LET fast neutrons. Two cell cycles post-irradiation, interferon-beta (IFNß), an immunogenic cytokine, and Trex1, an exonuclease that suppresses STING activation, were assayed. In parallel, cells were assayed at one cell cycle post-irradiation for micronucleus formation, an immunogenic marker of DNA damage, and for LaminA, a marker of micronucleus membrane rupture.

Results: Neutron-irradiated MCC13s produce more IFNß per dose, with peak IFNß ranging from 4-5.5Gy, in contrast to x-ray-irradiated cells with peak at 12-14Gy. The IFNß amplitude was not significantly different between modalities. The RBE for peak IFNß secretion (RBE_IFNß) was calculated to be 2.7, consistent with published models of neutron RBE for DSB induction. Trex1 was upregulated linearly with dose, with fourfold higher upregulation per dose from neutrons. Micronucleus formation at equivalent RBE-weighted doses was comparable between modalities. Fewer micronucleus ruptures were detected in neutron-irradiated MCC13s, a possible indication of prolonged cell cycle arrest.

Conclusion: High-LET neutrons are more efficient at eliciting pro-immunogenic factors, suggestive of enhanced potential to induce abscopal effects with adjuvant immunotherapy in vivo. However, immunosuppressive Trex1 transcription was induced at lower doses than x-ray irradiation, and optimal responses between modalities were comparable. Consideration of RBE_IFNß may potentially aid in radiotherapy planning with pro-immunogenic intent. Future work will explore dose delivery protocols to determine optimal dose and temporal aspects of fractionation to maximize immunogenic signals.

Funding Support, Disclosures, and Conflict of Interest: D. Miles was supported by the Purdue Doctoral Fellowship and Bilsland Dissertation Fellowship.


Radioimmunotherapy, RBE, LET


TH- Radiobiology(RBio)/Biology(Bio): RBio- Particle therapy- other

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