Details

Autor(en) / Beteiligte

• 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

Titel

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses

Ist Teil von

• Nature medicine, 2018-08, Vol.24 (8), p.1143-1150

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance 1 – 4 . This phenomenon has been implicated in chemorefractory small cell lung cancer 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′ 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. Retroelements located in antisense orientation within interferon-regulated genes are reactivated in a subset of cancer cells and initiate a STING- and MAVS-dependent feed-forward inflammatory loop, driving antitumor immunity and exhaustion.