- Cañadas, Israel;
- Thummalapalli, Rohit;
- Kim, Jong Wook;
- Kitajima, Shunsuke;
- Jenkins, Russell William;
- Christensen, Camilla Laulund;
- Campisi, Marco;
- Kuang, Yanan;
- Zhang, Yanxi;
- Gjini, Evisa;
- Zhang, Gao;
- Tian, Tian;
- Sen, Debattama Rai;
- Miao, Diana;
- Imamura, Yu;
- Thai, Tran;
- Piel, Brandon;
- Terai, Hideki;
- Aref, Amir Reza;
- Hagan, Timothy;
- Koyama, Shohei;
- Watanabe, Masayuki;
- Baba, Hideo;
- Adeni, Anika Elise;
- Lydon, Christine Anne;
- Tamayo, Pablo;
- Wei, Zhi;
- Herlyn, Meenhard;
- Barbie, Thanh Uyen;
- Uppaluri, Ravindra;
- Sholl, Lynnette Marie;
- Sicinska, Ewa;
- Sands, Jacob;
- Rodig, Scott;
- Wong, Kwok Kin;
- Paweletz, Cloud Peter;
- Watanabe, Hideo;
- Barbie, David Allen
Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, 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' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat 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 major histocompatibility complex 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 derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.