Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses

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 end...

Full description

Saved in:

Bibliographic Details
Published in:	Nature medicine Vol. 24; no. 8; pp. 1143 - 1150
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-08-2018 Nature Publishing Group
Subjects:	631/250/262 631/67/327 692/699/67/580 Animals Antisense therapy Axl protein Biological response modifiers Biomedical and Life Sciences Biomedicine Cancer Cancer cells Cancer immunotherapy Cancer Research Cancer treatment Care and treatment Cell Line, Tumor Chemotherapy Chromatin Cytokines Derepression Dosage and administration Double-stranded RNA Endogenous retroviruses Endogenous Retroviruses - drug effects Endogenous Retroviruses - metabolism Enzymes Feedback loops Gene expression Gene Expression Regulation, Neoplastic Gene regulation Gene sequencing Genes Genetic aspects Humans Immunity Immunity, Innate - drug effects Immunotherapy Infectious Diseases Innate immunity Interferon Interferon regulatory factor 3 Interferons - pharmacology Letter Long terminal repeat Lung cancer Major histocompatibility complex Mesenchyme Metabolic Diseases Mice, Nude Molecular Medicine Neoplasms - genetics Neoplasms - immunology Neoplasms - virology Neurosciences Positive feedback Retrovirus infections Retroviruses Ribonucleic acid Risk factors RNA RNA, Antisense - genetics Signaling Small cell lung cancer Small cell lung carcinoma Stat1 protein Stem cells Subpopulations Transcription Transcription (Genetics) Tumors γ-Interferon
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	These authors contributed equally to this work.
ISSN:	1078-8956 1546-170X
DOI:	10.1038/s41591-018-0116-5