Abstract 6105: Single high-dose irradiation induced iRhom2 up-regulation promotes macrophage anti-tumor activity through cGAS/STING signaling

Abstract

Abstract Clinical application of Stereotactic body radiotherapy (SBRT) allows high dose of radiation to be delivered to extracranial target within the body safely, however, high dose per fraction and with fewer fractions(hypofractionation) opened up the radiation oncology field to new questions on variety of dose-fractionation schedules, especially, the immunomodulatory effects of radiotherapy, which changes following the variety of dose-fractionation schedules. In the present study, we excluded the direct antitumor effect of radiation by comparing three different fractionation schedules –8*2Gy, 3*4.5Gy, 1*10Gy, which have the same biologically effective dose (BED). We found the fractionation schedules 1*10Gy had a significant higher antitumor effect, suggesting that a single high-dose induced a more enhanced anti-tumor immunity compared to the conventionally fractionation(8*2Gy) and moderately fractionation (3*4.5Gy). However, in STING deficiency mice, we failed to find a different tumor control effect among the three dose-fractionation schedules, suggesting cGAS/STING signaling was involved in regulating immunomodulatory effects that leading to different anti-tumor immunity. Further mechanism investigation revealed that single high-dose irradiation induced up-regulation of iRhom2 in infiltrated macrophage, and iRhom2 promoted cGAS/STING signaling via maintaining stability of STING and facilitating STING trafficking from ER to perinuclear microsomes. Meanwhile, a positive feedback loop between iRhom2 and TNFα sharpened the signaling responses, and amplified antitumor immunity induced by cGAS-STING-IFN pathway after single high-dose irradiation. Taken together, these results suggest that single high-dose irradiation induced iRhom2 up-regulation promotes macrophage anti-tumor activity through cGAS/STING signaling. Citation Format: Xiaomei Zhao, Shisuo Du, Biao Wang, Zhaochong Zeng. Single high-dose irradiation induced iRhom2 up-regulation promotes macrophage anti-tumor activity through cGAS/STING signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6105.