TY - JOUR
T1 - Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses
AU - Cañadas, Israel
AU - Thummalapalli, Rohit
AU - Kim, Jong Wook
AU - Kitajima, Shunsuke
AU - Jenkins, Russell William
AU - Christensen, Camilla Laulund
AU - Campisi, Marco
AU - Kuang, Yanan
AU - Zhang, Yanxi
AU - Gjini, Evisa
AU - Zhang, Gao
AU - Tian, Tian
AU - Sen, Debattama Rai
AU - Miao, Diana
AU - Imamura, Yu
AU - Thai, Tran
AU - Piel, Brandon
AU - Terai, Hideki
AU - Aref, Amir Reza
AU - Hagan, Timothy
AU - Koyama, Shohei
AU - Watanabe, Masayuki
AU - Baba, Hideo
AU - Adeni, Anika Elise
AU - Lydon, Christine Anne
AU - Tamayo, Pablo
AU - Wei, Zhi
AU - Herlyn, Meenhard
AU - Barbie, Thanh Uyen
AU - Uppaluri, Ravindra
AU - Sholl, Lynnette Marie
AU - Sicinska, Ewa
AU - Sands, Jacob
AU - Rodig, Scott
AU - Wong, Kwok Kin
AU - Paweletz, Cloud Peter
AU - Watanabe, Hideo
AU - Barbie, David Allen
N1 - Funding Information:
We thank J. Albanell, A. Rovira, and E. Arriola (Hospital del Mar Medical Research Institute, Barcelona, Spain) for providing human SCLC cell lines and the H69/H69M cell model. We also thank W.G. Kaelin, Jr. (Dana–Farber Cancer Institute, Boston, MA) for providing human ccRCC cell lines. This work was supported by NCI-R01 CA190394-02 and NIH-U01 CA2143A1-01 (D.A.B.), the Gloria T. Maheu, Steven J. Schaubert, and Heerwagen Family Funds for Lung Cancer Research (D.A.B.), the Rising Tide Foundation (D.A.B.), NIH-U01 CA217885 (J.W.K., P.T.), NIH/NCI P01CA120964 (K.K.W.), 5R01CA163896-04 (K.K.W.), 5R01CA140594-07 (K.K.W.), 5R01CA122794-10 (K.K.W.), 5R01CA166480-04 (K.K.W.), the Gross-Loh Family Fund for Lung Cancer Research (K.K.W., D.A.B.), and the Susan Spooner Family Lung Cancer Research Fund at Dana–Farber Cancer Institute (K.K.W.). Additional funding was provided by NIH grants P01 CA114046, P01 CA025874, P30 CA010815, and R01 CA047159 and by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Melanoma Research Foundation. The support for Shared Resources used in this study was provided by Cancer Center Support Grant CA010815 (to The Wistar Institute). Additional support from a Stand Up To Cancer–American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2CAACR-DT1715). Stand Up to Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. R.T. is a Howard Hughes Medical Institute Medical Research Fellow.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/8/1
Y1 - 2018/8/1
N2 - 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.
AB - 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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U2 - 10.1038/s41591-018-0116-5
DO - 10.1038/s41591-018-0116-5
M3 - Article
C2 - 30038220
AN - SCOPUS:85050517648
SN - 1078-8956
VL - 24
SP - 1143
EP - 1150
JO - Nature Medicine
JF - Nature Medicine
IS - 8
ER -