作者
Israel Cañadas,Rohit Thummalapalli,Jong Wook Kim,Shunsuke Kitajima,Russell W. Jenkins,Camilla L. Christensen,Marco Campisi,Yanan Kuang,Yanxi Zhang,Evisa Gjini,Gao Zhang,Tian Tian,Debattama R. Sen,Diana Miao,Yu Imamura,Tran C. Thai,Brandon Piel,Hideki Terai,Amir Reza Aref,Timothy Hagan,Shohei Koyama,Masayuki Watanabe,Hideo Baba,Anika E. Adeni,Christine Lydon,Pablo Tamayo,Zhi Wei,Meenhard Herlyn,Thanh U. Barbie,Ravindra Uppaluri,Lynnette Marie Sholl,Ewa Sicińska,Jacob Sands,Scott J. Rodig,Kwok Kin Wong,Cloud P. Paweletz,Hideo Watanabe,David A. Barbie
摘要
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. Retroelements located in antisense orientation within interferon-regulated genes are reactivated in a subset of cancer cells and initiate a STING- and MAVS-dependent feed-forward inflammatory loop, driving antitumor immunity and exhaustion.