Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.
Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.
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由特异性干扰素刺激的内源性逆转录病毒引发的肿瘤固有免疫。
DOI：
10.1038/s41591-018-0116-5
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发表时间：
2018-08
期刊：
影响因子：
82.9
通讯作者：
Barbie DA
中科院分区：
文献类型：
--
作者：
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
间充质肿瘤亚群分泌促肿瘤细胞因子并促进治疗抵抗。这种现象与化疗难治性小细胞肺癌（SCLC）和对靶向治疗的耐药性有关，但仍未完全确定。在这里，我们鉴定了内源性逆转录病毒（erv）的一个亚类，它在这些细胞中参与先天免疫信号。受刺激的3 Prime反义逆转录病毒编码序列（SPARCS）在STAT1和EZH2调控富集的特定基因的3 ' utr中反向定向。由于stat1激活基因启动子和反义ERV的5 ' LTR的双向转录，这些基因座的去抑制导致IFNγ暴露后产生dsRNA。MAVS和STING的结合激活下游TBK1、IRF3和STAT1信号，维持正反馈循环。SPARCS在人类肿瘤中的诱导与MHC 1类表达、间充质标记物和染色质修饰酶（包括EZH2）的下调密切相关。对SPARCS高诱导表达细胞系的分析显示，SPARCS与AXL/MET阳性间充质细胞状态密切相关。虽然SPARCS高肿瘤是免疫浸润的，但它们也表现出免疫抑制微环境的多种特征。总之，这些数据揭示了erv的一个亚类，其去抑制触发癌症中的病理性先天免疫信号，对癌症免疫治疗具有重要意义。
Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance. This phenomenon has been implicated in chemorefractory small cell lung cancer (SCLC) 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′UTRs of specific genes enriched for regulation by STAT1 and EZH2. De-repression of these loci results in dsRNA generation following IFNγ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5′ LTR 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 MHC 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 de-repression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.
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影响因子：
64.8
作者：
Manguso RT;Pope HW;Zimmer MD;Brown FD;Yates KB;Miller BC;Collins NB;Bi K;LaFleur MW;Juneja VR;Weiss SA;Lo J;Fisher DE;Miao D;Van Allen E;Root DE;Sharpe AH;Doench JG;Haining WN
通讯作者：
Haining WN
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
64.8
作者：
Marusyk, Andriy;Tabassum, Doris P.;Altrock, Philipp M.;Almendro, Vanessa;Michor, Franziska;Polyak, Kornelia
通讯作者：
Polyak, Kornelia
DOI：
10.1126/science.aan5951
发表时间：
2018-02-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Miao D;Margolis CA;Gao W;Voss MH;Li W;Martini DJ;Norton C;Bossé D;Wankowicz SM;Cullen D;Horak C;Wind-Rotolo M;Tracy A;Giannakis M;Hodi FS;Drake CG;Ball MW;Allaf ME;Snyder A;Hellmann MD;Ho T;Motzer RJ;Signoretti S;Kaelin WG Jr;Choueiri TK;Van Allen EM
通讯作者：
Van Allen EM
DOI：
10.1126/science.aad5497
发表时间：
2016-03-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chuong EB;Elde NC;Feschotte C
通讯作者：
Feschotte C