Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses

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.

Expressional activation and functional roles of human endogenous retroviruses in cancers

“…Besides the expression of HERVs induced by DNA methylation inhibitors, some specific genes were identified to be associated with the induction of HERV‐derived dsRNAs. Cañadas et al found that expression of a novel subclass of ERVs was triggered in mesenchymal tumor subpopulations with high AXL/MET expression and low EZH2 levels when exposed to IFN‐γ . Expression of such ERVs promoted MHC class 1 upregulation, T‐cell infiltration, activation of immune checkpoints, and myeloid infiltration, thus promoting tumor immune suppression.…”

“…Cañadas et al found that expression of a novel subclass of ERVs was triggered in mesenchymal tumor subpopulations with high AXL/MET expression and low EZH2 levels when exposed to IFN-γ. 142…”

Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer

“…While these results are not sufficient to conclude that Tbk1 loss promotes antitumor immunity in PDA, the idea is not unreasonable given that Tbk1 Δ/Δ mice have been shown to produce higher levels of pro-inflammatory cytokines in response to immune challenge [12]. In agreement with the notion that Tbk1 loss produces antitumor immunity, two recent studies reported that immune evasion and metastatic behavior are highly associated with the engagement of the cGAS-STING-TBK1 innate immune pathway in cancer cells [50][51][52]. In the first study, Backhoum et al [51] found that chromosomal instability in cancer cells, caused by errors in chromosomal segregation during mitosis, promoted cellular invasion and metastasis through the introduction of double-stranded DNA into the cytosol, engaging the cGAS-STING-TBK1 antiviral pathway.…”

“…In the first study, Backhoum et al [51] found that chromosomal instability in cancer cells, caused by errors in chromosomal segregation during mitosis, promoted cellular invasion and metastasis through the introduction of double-stranded DNA into the cytosol, engaging the cGAS-STING-TBK1 antiviral pathway. In the second report, Cañadas et al [52] characterized an interferonstimulated positive feedback loop of antisense endogenous retroviruses (ERVs) present in a number of human cancer cell lines that produced hyperactive innate immune signaling, myeloid cell infiltration, and immune checkpoint activation. Additionally, they discovered that high ERV-expressing cancer cells correlate with an Axl-positive mesenchymal state, which is consistent with our observations [52].…”

“…In the second report, Cañadas et al [52] characterized an interferonstimulated positive feedback loop of antisense endogenous retroviruses (ERVs) present in a number of human cancer cell lines that produced hyperactive innate immune signaling, myeloid cell infiltration, and immune checkpoint activation. Additionally, they discovered that high ERV-expressing cancer cells correlate with an Axl-positive mesenchymal state, which is consistent with our observations [52].…”