Loss of ADAR1 in tumor cells activates cDC1s and sensitizes pancreatic cancer to immunotherapy

Pancreatic cancer is notoriously resistant to immunotherapy, primarily due to inadequate antigen presentation and the exclusion of immunogenic cells from the tumor microenvironment. Strategies to enhance antigen presentation and promote the infiltration of cytotoxic CD8+ T cells may improve the efficacy of immunotherapy in pancreatic cancer. In this study, we show that ADAR1 is overexpressed in pancreatic cancer, and higher ADAR1 expression correlates with poorer survival outcomes in patients. Depletion of ADAR1 in tumor cells leads to an accumulation of endogenous double-stranded RNA (dsRNA), which triggers the MDA5-mediated type I interferon (IFN) response and results in excessive IFNß production. Tumor-derived IFNß then promotes the recruitment and activation of cDC1s, thereby enhancing CD8+ T cell infiltration and activation, and ultimately sensitizing pancreatic cancer to CD8+ T cell-based immunotherapy. These findings suggest that combining ADAR1 inhibition with immunotherapy may offer a promising therapeutic strategy for pancreatic cancer. Overall design: For RNA-seq analysis of FC1199 cells, control, Adar1-null or ADAR1/STAT1 DKO FC1199 cells were stimulated with IFN? (10 ng/ml, Peprotech) for 24 hours. RNA was extracted from cell pellets using Trizol (Takara). Poly(A) RNA was isolated from 1 µg of total RNA to generate cDNA libraries following the TruSeq™ RNA Sample Prep Kit protocol. The libraries were then sequenced using the Illumina NovaSeq 6000 platform. For RNA-seq data analysis, paired-end clean reads were aligned to the mouse reference genome (GRCm39) using Hisat2. Aligned reads were quantified for mRNA expression using featureCounts. Differential expression analysis and data normalization were performed with DESeq2.