Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses

Document Type

Article

Publication Date

8-1-2018

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-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.

Identifier

85050517648 (Scopus)

Publication Title

Nature Medicine

External Full Text Location

https://doi.org/10.1038/s41591-018-0116-5

e-ISSN

1546170X

ISSN

10788956

PubMed ID

30038220

First Page

1143

Last Page

1150

Issue

8

Volume

24

Grant

CA010815

Fund Ref

National Cancer Institute

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