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

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-? 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.

SUBMITTER: Canadas I

PROVIDER: S-EPMC6082722 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Cañadas Israel I Thummalapalli Rohit R Kim Jong Wook JW Kitajima Shunsuke S Jenkins Russell William RW Christensen Camilla Laulund CL Campisi Marco M Kuang Yanan Y Zhang Yanxi Y Gjini Evisa E Zhang Gao G Tian Tian T Sen Debattama Rai DR Miao Diana D Imamura Yu Y Thai Tran T Piel Brandon B Terai Hideki H Aref Amir Reza AR Hagan Timothy T Koyama Shohei S Watanabe Masayuki M Baba Hideo H Adeni Anika Elise AE Lydon Christine Anne CA Tamayo Pablo P Wei Zhi Z Herlyn Meenhard M Barbie Thanh Uyen TU Uppaluri Ravindra R Sholl Lynnette Marie LM Sicinska Ewa E Sands Jacob J Rodig Scott S Wong Kwok Kin KK Paweletz Cloud Peter CP Watanabe Hideo H Barbie David Allen DA

Nature medicine 20180723 8

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance<sup>1-4</sup>. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies<sup>5-8</sup>, 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' untranslat ...[more]

PMID: 30038220

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Project description:About 8% of our genome is composed of sequences with viral origin, namely human Endogenous Retroviruses (HERVs). HERVs are relics of ancient infections that affected the primates' germ line along the last 100 million of years, and became stable elements at the interface between self and foreign DNA. Intriguingly, HERV co-evolution with the host led to the domestication of activities previously devoted to the retrovirus life cycle, providing novel cellular functions. For example, selected HERV envelope proteins have been coopted for pregnancy-related purposes, and proviral Long Terminal Repeats participate in the transcriptional regulation of various cellular genes. Given the HERV persistence in the host genome and its basal expression in most healthy tissues, it is reasonable that human defenses should prevent HERV-mediated immune activation. Despite this, HERVs and their products (including RNA, cytosolic DNA, and proteins) are still able to modulate and be influenced by the host immune system, fascinatingly suggesting a central role in the evolution and functioning of the human innate immunity. Indeed, HERV sequences had been major contributors in shaping and expanding the interferon network, dispersing inducible genes that have been occasionally domesticated in various mammalian lineages. Also the HERV integration within or near to genes encoding for critical immune factors has been shown to influence their activity, or to be responsible for their polymorphic variation in the human population, such as in the case of an HERV-K(HML10) provirus in the major histocompatibility complex region. In addition, HERV expressed products have been shown to modulate innate immunity effectors, being therefore often related on the one side to inflammatory and autoimmune disorders, while on the other side to the control of excessive immune activation through their immunosuppressive properties. Finally, HERVs have been proposed to establish a protective effect against exogenous infections. The present review summarizes the involvement of HERVs and their products in innate immune responses, describing how their intricate interplay with the first line of human defenses can actively contribute either to the host protection or to his damage, implying a subtle balance between the persistence of HERV expression and the maintenance of a basal immune alert.

Dataset Information

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

Publications

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

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