Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.
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Cañadas Israel, Thummalapalli Rohit, Kim Jong Wook, Kitajima Shunsuke, Jenkins Russell William, Christensen Camilla Laulund, Campisi Marco, Kuang Yanan, Zhang Yanxi, Gjini Evisa, Zhang Gao, Tian Tian, Sen Debattama Rai, Miao Diana, Imamura Yu, Thai Tran, Piel Brandon, Terai Hideki, Aref Amir Reza, Hagan Timothy, Koyama Shohei, Watanabe Masayuki, Baba Hideo, Adeni Anika Elise, Lydon Christine Anne, Tamayo Pablo, Wei Zhi, Herlyn Meenhard, Barbie Thanh Uyen, Uppaluri Ravindra, Sholl Lynnette Marie, Sicinska Ewa, Sands Jacob, Rodig Scott, Wong Kwok Kin, Paweletz Cloud Peter, Watanabe Hideo, Barbie David Allen
Аннотация
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.