학술논문
Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses
Document Type
article
Author
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
Source
Nature Medicine. 24(8)
Subject
Language
Abstract
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.