Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses
In: Nature Medicine, Jg. 24 (2018-08-01), Heft 8
academicJournal
- 1143 - 1150
Zugriff:
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.
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Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses
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Autor/in / Beteiligte Person: | 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 |
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Zeitschrift: | Nature Medicine, Jg. 24 (2018-08-01), Heft 8 |
Veröffentlichung: | eScholarship, University of California, 2018 |
Medientyp: | academicJournal |
Umfang: | 1143 - 1150 |
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