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Nat Med. 2018 Aug;24(8):1143-1150. doi: 10.1038/s41591-018-0116-5. Epub 2018 Jul 23.

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
3
Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
4
Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
5
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
6
Melanoma Research Center and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
7
Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA.
8
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
9
Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
10
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
11
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
12
Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan.
13
Moores Cancer Center and School of Medicine, University of California San Diego, La Jolla, CA, USA.
14
Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
15
Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
16
Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
17
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
18
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. dbarbie@partners.org.

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.

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