Abstract A16: RIG-I-mediated cell death pathways activated by PAMP RNA in hepatic tumor cells


 Most malignant cells are poorly immunogenic and fail to elicit an effective antitumor response. However, some viral infections of cancer cells can trigger intracellular innate immune defenses that initiate cancer cell death, known as “oncolytic signaling.” Our lab has identified a viral pathogen associated molecular pattern (PAMP) RNA motif from the hepatitis C virus (HCV) genome that is recognized by the pathogen recognition receptor, retinoic acid-inducible gene I (RIG-I), to induce innate immune signaling when delivered to cells in a liposomal formulation. We found that PAMP RNA can direct RIG-I-dependent signaling to drive cell death in tumor cells, indicating that PAMP activation of the RIG-I pathway has applications for oncolytic destruction of tumors. However, the exact cell death pathways that are activated by PAMP are not clearly defined. We hypothesize that PAMP activates a RIG-I-mediated form of apoptosis and that cancer cells are more susceptible than non-cancer cells to death by this apoptotic pathway. In vitro studies using CRISPR knockout cell lines confirmed that PAMP-induced cell death signaling requires RIG-I, mitochondrial antiviral-signaling protein (MAVS), and interferon regulatory factor 3 (IRF3). Further, our analyses show that PAMP-induced cell death is regulated by type 1 interferon, and that cell death outcomes can be blocked by treatment of cells with caspase inhibitor. Thus, PAMP-induced RIG-I signaling triggers cell death through linkage with caspase signaling. This research will define cell death pathways activated by PAMP and RIG-I signaling by interrogating multiple cell death programs and will reveal the potential of designing antitumor therapeutics leveraging PAMP.
 Citation Format: Brittany Ulloa, Michael Gale. RIG-I-mediated cell death pathways activated by PAMP RNA in hepatic tumor cells [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A16.