Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses (ATAC-seq)

Mesenchymal tumor subclones secrete cytokines that promote tumorigenesis and chemoresistance, but the mechanism that underlies this phenomenon remains poorly understood. Here we identify a de-repressed subclass of endogenous retroviruses (ERVs) that engage innate immune signaling in mesenchymal cancer cells. These Stimulated 3 Prime Antisense Retroviral Coding Sequences (SPARCS) are oriented inversely in 3’UTRs of certain interferon-inducible genes, generating dsRNA following IFN exposure. Sensing of this dsRNA by MAVS fuels activation of TBK1, IRF3, and STAT1 signaling. SPARCS induction in human tumors is tightly associated with B2M and MHC class 1 antigen expression, mesenchymal markers, and downregulation of chromatin modifying enzymes. Cell lines poised to induce high levels of SPARCS expression are associated with an AXL positive mesenchymal cell state. These data unveil a novel subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer. Examination of chromatin accessibility in H69 and H69AR cells