Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance(1–4). This phenomenon has been implicated in chemorefractory small cell lung cancer (SCLC) and resistance to targeted therapies(5–8), but remains incompletely defined. Here we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 Prime Antisense Retroviral Coding Sequences (SPARCS) are oriented inversely in 3′UTRs of specific genes enriched for regulation by STAT1 and EZH2. De-repression of these loci results in dsRNA generation following IFNγ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5′ LTR of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with MHC class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET positive mesenchymal cell state. While SPARCS high tumors are immune infiltrated, they also exhibit multiple features of an immune suppressed microenviroment. Together, these data unveil a subclass of ERVs whose de-repression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.