Abstract LT07: HEPATOCTYE-MACROPHAGE CROSSTALK VIA THE PGRN-EGFR AXIS MODULATES ADAR1-MEDIATED IMMUNITY IN THE LIVER

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Abstract ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signalling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, Progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signalling and attracting EGFR+ macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1high tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion. Citation Format: Wei Liang Gan, Xi Ren, Vanessa Hui En Ng, Larry Ng, Yangyang Song, Vincent Tano, Jian Han, Omer An, Jinghe Xie, Bryan Y.L. Ng, Daryl Jin Tai Tay, Sze Jing Tang, Haoqing Shen, Shruti Khare, Kelvin Han Chung Chong, Dan Yock Young, Bin Wu, Ramanuj DasGupta, Leilei Chen. HEPATOCTYE-MACROPHAGE CROSSTALK VIA THE PGRN-EGFR AXIS MODULATES ADAR1-MEDIATED IMMUNITY IN THE LIVER [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr LT07.

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