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Article: Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses

TitleTumor innate immunity primed by specific interferon-stimulated endogenous retroviruses
Authors
Issue Date2018
Citation
Nature Medicine, 2018, v. 24, n. 8, p. 1143-1150 How to Cite?
AbstractMesenchymal 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.
Persistent Identifierhttp://hdl.handle.net/10722/318721
ISSN
2023 Impact Factor: 58.7
2023 SCImago Journal Rankings: 19.045
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorCañadas, Israel-
dc.contributor.authorThummalapalli, Rohit-
dc.contributor.authorKim, Jong Wook-
dc.contributor.authorKitajima, Shunsuke-
dc.contributor.authorJenkins, Russell William-
dc.contributor.authorChristensen, Camilla Laulund-
dc.contributor.authorCampisi, Marco-
dc.contributor.authorKuang, Yanan-
dc.contributor.authorZhang, Yanxi-
dc.contributor.authorGjini, Evisa-
dc.contributor.authorZhang, Gao-
dc.contributor.authorTian, Tian-
dc.contributor.authorSen, Debattama Rai-
dc.contributor.authorMiao, Diana-
dc.contributor.authorImamura, Yu-
dc.contributor.authorThai, Tran-
dc.contributor.authorPiel, Brandon-
dc.contributor.authorTerai, Hideki-
dc.contributor.authorAref, Amir Reza-
dc.contributor.authorHagan, Timothy-
dc.contributor.authorKoyama, Shohei-
dc.contributor.authorWatanabe, Masayuki-
dc.contributor.authorBaba, Hideo-
dc.contributor.authorAdeni, Anika Elise-
dc.contributor.authorLydon, Christine Anne-
dc.contributor.authorTamayo, Pablo-
dc.contributor.authorWei, Zhi-
dc.contributor.authorHerlyn, Meenhard-
dc.contributor.authorBarbie, Thanh Uyen-
dc.contributor.authorUppaluri, Ravindra-
dc.contributor.authorSholl, Lynnette Marie-
dc.contributor.authorSicinska, Ewa-
dc.contributor.authorSands, Jacob-
dc.contributor.authorRodig, Scott-
dc.contributor.authorWong, Kwok Kin-
dc.contributor.authorPaweletz, Cloud Peter-
dc.contributor.authorWatanabe, Hideo-
dc.contributor.authorBarbie, David Allen-
dc.date.accessioned2022-10-11T12:24:24Z-
dc.date.available2022-10-11T12:24:24Z-
dc.date.issued2018-
dc.identifier.citationNature Medicine, 2018, v. 24, n. 8, p. 1143-1150-
dc.identifier.issn1078-8956-
dc.identifier.urihttp://hdl.handle.net/10722/318721-
dc.description.abstractMesenchymal 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.-
dc.languageeng-
dc.relation.ispartofNature Medicine-
dc.titleTumor innate immunity primed by specific interferon-stimulated endogenous retroviruses-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/s41591-018-0116-5-
dc.identifier.pmid30038220-
dc.identifier.scopuseid_2-s2.0-85050517648-
dc.identifier.volume24-
dc.identifier.issue8-
dc.identifier.spage1143-
dc.identifier.epage1150-
dc.identifier.eissn1546-170X-
dc.identifier.isiWOS:000440955500020-
dc.identifier.f1000733679701-

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