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.

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses / Canadas, I.; Thummalapalli, R.; Kim, J. W.; Kitajima, S.; Jenkins, R. W.; Christensen, C. L.; Campisi, M.; Kuang, Y.; Zhang, Y.; Gjini, E.; Zhang, G.; Tian, T.; Sen, D. R.; Miao, D.; Imamura, Y.; Thai, T.; Piel, B.; Terai, H.; Aref, A. R.; Hagan, T.; Koyama, S.; Watanabe, M.; Baba, H.; Adeni, A. E.; Lydon, C. A.; Tamayo, P.; Wei, Z.; Herlyn, M.; Barbie, T. U.; Uppaluri, R.; Sholl, L. M.; Sicinska, E.; Sands, J.; Rodig, S.; Wong, K. K.; Paweletz, C. P.; Watanabe, H.; Barbie, D. A.. - In: NATURE MEDICINE. - ISSN 1546-170X. - 24:8(2018), pp. 1143-1150. [10.1038/s41591-018-0116-5]

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses

Campisi M.;
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.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11583/2852397