Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses

I Caņadas, R Thummalapalli, JW Kim, S Kitajima… - Nature medicine, 2018 - nature.com
I Caņadas, R Thummalapalli, JW Kim, S Kitajima, RW Jenkins, CL Christensen, M Campisi
Nature medicine, 2018nature.com
Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote
treatment resistance,,–. This phenomenon has been implicated in chemorefractory small cell
lung cancer and resistance to targeted therapies,,–, 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 …
Abstract
Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance, , –. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies, , –, 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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