Activation of STING in response to partial-tumor radiation exposure

Purpose: To determine the mechanisms involved in partial volume radiation therapy (RT)-induced tumor response. Methods and Materials: We investigated 67NR murine orthotopic breast tumors in Balb/c mice and Lewis lung carcinoma (LLC cells; WT, Crispr/Cas9 Sting KO and Atm KO) injected in the flank of C57Bl/6, cGAS or STING KO mice. RT was delivered to 50% or 100% of the tumor volume using a 2X2 cm collimator on a microirradiator allowing precise irradiation. Tumors and blood were collected at different time points post-RT and assessed for cytokine measurements. Results: There is a significant activation of the cGAS/STING pathway in the hemi-irradiated tumors as compared to control and to 100% exposed 67NR tumors. In the LLC model, we determined that an ATM-mediated non-canonical activation of STING is involved. We demonstrated that the partial exposure RT-mediated immune response is dependent on ATM activation in the tumor cells and on the STING activation in the host, while cGAS is dispensable. Our results also indicate that partial volume RT stimulates a different cytokine expression as compared to 100% tumor volume exposure. Conclusion: Partial volume RT induces an anti-tumor response by activating STING which stimulates a specific cytokine signature as part of the immune response. However, the mechanism of this STING activation, via the canonical cGAS/STING pathway or a non-canonical ATM-driven pathway, depends on the tumor type. Identifying the upstream pathways responsible for STING activation in the partial RT-mediated immune response in different tumor types would improve this therapy and its potential combination with immune checkpoint blockade and other anti-tumor therapies.