Abstract PR011: TXNRD1 drives innate immune response in senescent cells to promote tumor immune surveillance and age-associated inflammation

Abstract Cellular senescence regulates cancer and tissue aging in part through the secretion of proinflammatory factors known as the senescence-associated secretory phenotype (SASP). For example, sterile inflammation or ‘inflammaging’ is a hallmark of tissue aging. Thioredoxin reductase 1 (TXNRD1) genetic variability is associated with aging and is often upregulated in human cancers. TXNRD1’s role in regulating tissue aging and cancer has been attributed to its enzymatic role in regulating cellular redox. Here we show that TXNRD1 drives the SASP and inflammation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragments (CCF) and interacts with cGAS in a senescence status dependent manner, which is required for the SASP. Biochemically, TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 is required for both the tumor-promoting and immune-surveillance functions of senescent cells, which are mediated by the SASP in vivo in mouse tumor models. Treatment of aged mice with a TXNRD1 inhibitor that disrupts its interaction with cGAS, but not an inhibitor of its enzymatic activity alone, downregulated inflammaging in several tissues. In summary, our results report TXNRD1 promotes inflammation via activating the innate immune response in a manner depending on its interaction with cGAS but not its enzymatic activity. Our findings have important implications for both tissue aging and cancer. Citation Format: Xue Hao, Bo Zhao, Martina Towers, Liping Liao, Hsin Yao Tang, Aaron Havas, Andrew V. Kossenkov, Shelley Berger, Peter D. Adams, David W. Speicher, Rugang Zhang. TXNRD1 drives innate immune response in senescent cells to promote tumor immune surveillance and age-associated inflammation [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR011.