Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms [PDAClines_RNAseq]

To thrive, cancers must navigate acute inflammatory signaling accompanying oncogenic transformation, such as via overexpression of retrotransposable elements. We examined the relationship between immunostimulatory repeat expression, tumor evolution and the tumor-immune microenvironment. Integration of multimodal data from a cohort of pancreatic ductal adenocarcinoma (PDAC) patients revealed expression of specific Alu repeats predicted to form double-stranded RNA (dsRNAs) and trigger RIG-I-like receptor-associated (RLR) type-I interferon (IFN) signaling. Alu-derived dsRNA anti-correlated with pro-tumorigenic macrophage infiltration. We defined two complementary pathways whereby PDAC may adapt to such anti-tumorigenic signaling. In mutant p53 tumors, ORF1p from LINE-1 preferentially binds Alus and decreases their expression, whereas ADAR1 editing primarily reduces dsRNA formation in wild-type p53 tumors. Depletion of either ORF1p or ADAR1 reduced tumor growth in vitro. That tumors utilize multiple pathways to mitigate immunostimulatory repeats implies that the stress from their expression is a fundamental phenomenon to which PDAC, and other tumors, adapt.