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

Lung Cancer Autophagy

Lung Cancer Autophagy (Source: NCI / Massey Cancer Center at Virginia Commonwealth University; Creator: David A. Gewirtz and Tareq Saleh)

Cañadas I, Thummalapalli R, Kim JW, Kitajima S, Jenkins RW, Christensen CL, Campisi M, Kuang Y, Zhang Y, Gjini E, Zhang G, Tian T, Sen DR, Miao D, Imamura Y, Thai T, Piel B, Terai H, Aref AR, Hagan T, Koyama S, Watanabe M, Baba H, Adeni AE, Lydon CA, Tamayo P, Wei Z, Herlyn M, Barbie TU, Uppaluri R, Sholl LM, Sicinska E, Sands J, Rodig S, Wong KK, Paweletz CP, Watanabe H, Barbie DA

Nature Medicine

July 23, 2018

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.

Last updated: August 03, 2018