Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses

Israel Cañadas, Rohit Thummalapalli, Jong Wook Kim, Shunsuke Kitajima, Russell William Jenkins, Camilla Laulund Christensen, Marco Campisi, Yanan Kuang, Yanxi Zhang, Evisa Gjini, Gao Zhang, Tian Tian, Debattama Rai Sen, Diana Miao, Yu Imamura, Tran Thai, Brandon Piel, Hideki Terai, Amir Reza Aref, Timothy HaganShohei Koyama, Masayuki Watanabe, Hideo Baba, Anika Elise Adeni, Christine Anne Lydon, Pablo Tamayo, Zhi Wei, Meenhard Herlyn, Thanh Uyen Barbie, Ravindra Uppaluri, Lynnette Marie Sholl, Ewa Sicinska, Jacob Sands, Scott Rodig, Kwok Kin Wong, Cloud Peter Paweletz, Hideo Watanabe, David Allen Barbie

Research output: Contribution to journalArticlepeer-review

184 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1143-1150
Number of pages8
JournalNature Medicine
Issue number8
StatePublished - Aug 1 2018

All Science Journal Classification (ASJC) codes

  • General Biochemistry, Genetics and Molecular Biology


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