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

Nat Med
Authors
Keywords
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.

Year of Publication
2018
Journal
Nat Med
Volume
24
Issue
8
Pages
1143-1150
Date Published
2018 08
ISSN
1546-170X
DOI
10.1038/s41591-018-0116-5
PubMed ID
30038220
PubMed Central ID
PMC6082722
Links
Grant list
P01 CA025874 / CA / NCI NIH HHS / United States
R01 CA122794 / CA / NCI NIH HHS / United States
P30 CA010815 / CA / NCI NIH HHS / United States
R01 CA163896 / CA / NCI NIH HHS / United States
R01 CA166480 / CA / NCI NIH HHS / United States
R01 CA140594 / CA / NCI NIH HHS / United States
U01 CA213333 / CA / NCI NIH HHS / United States
R01 CA190394 / CA / NCI NIH HHS / United States
U01 CA217885 / CA / NCI NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
U24 CA194107 / CA / NCI NIH HHS / United States
P01 CA114046 / CA / NCI NIH HHS / United States
R01 CA047159 / CA / NCI NIH HHS / United States
K99 CA201618 / CA / NCI NIH HHS / United States
U01 CA214381 / CA / NCI NIH HHS / United States