期刊
NATURE MEDICINE
卷 24, 期 8, 页码 1143-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-018-0116-5
关键词
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资金
- NCI [R01 CA190394-02]
- NIH [U01 CA2143A1-01, U01 CA217885, P01 CA114046, P01 CA025874, P30 CA010815, R01 CA047159]
- Gloria T. Maheu, Steven J. Schaubert, and Heerwagen Family Funds for Lung Cancer Research
- Rising Tide Foundation
- NIH/NCI [P01CA120964, 5R01CA163896-04, 5R01CA140594-07, 5R01CA122794-10, 5R01CA166480-04]
- Gross-Loh Family Fund for Lung Cancer Research
- Susan Spooner Family Lung Cancer Research Fund at Dana-Farber Cancer Institute
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Melanoma Research Foundation
- Cancer Center Support Grant [CA010815]
- Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant [SU2CAACR-DT1715]
- American Association for Cancer Research, the Scientific Partner of SU2C
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 therapiess(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-gamma 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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