Role of ADAR1 loss in lung cancer on anti-tumor immunity and tumor cell growth via the RIG-I/MDA5-MAVS pathway.

Abstract

e20599 Background: Aberrant accumulation of dsDNA in tumour cells activates the cGAS-STING pathway, playing a crucial role in anti-tumour immunity. However, the role of the dsRNA sensor RIG-I-like receptor-mitochondrial antiviral signalling protein (RLR-MAVS) in anti-tumour immunity remains unclear. ADAR1 edits endogenous dsRNA by catalysing the deamination of adenosine to inosine, preventing activation of the RLR-MAVS pathway, which is vital for immune homeostasis and tissue development.In this study, we investigated the roles of ADAR1 and RLR-MAVS in anti-tumour immunity in lung cancer. Methods: CRISPR-Cas9 gene knockout technology was used to establish ADAR1 alone or combination knockout lung cancer cell, RNA-seq, qRT-PCR and Western blot were used to detect ISG expression and TBK1-IRF3 pathway. C57BL/6J xenograft model were used to elevate in vivo growth of ADAR1 alone or combination knockout lung cancer cell. And flow cytometry was used to detect immune activity of C57BL/6J mouse. Results: Our findings revealed that knocking out ADAR1 induces dsRNA accumulation, activating the TBK1-IRF3 pathway and stimulating ISG expression, which in turn activates anti-tumour immunity and suppresses lung cancer growth. We demonstrated that the RIG-I/MDA5-MAVS pathway is responsible for this anti-tumour immune activation and tumour suppression, whereas another downstream molecule of ADAR1, ZBP1, is not involved in this process. Moreover, we found that ADAR1-deficient lung cancer cells suppress abscopal homogeneous and non-homogeneous tumour growth when used as a tumour cell vaccine. Additionally, ADAR1 deficiency in lung cancer cells significantly enhances the efficacy of immunotherapy when employed as an adjuvant. Conclusions: In summary, our study elucidates the mechanism by which ADAR1 deficiency activates anti-tumour immunity and inhibits tumour cell growth. These findings highlight ADAR1 and the downstream RIG-I/MDA5-MAVS pathway as promising targets for immunotherapy development.