LincRNA-immunity landscape analysis identifies EPIC1 as a regulator of tumor immune evasion and immunotherapy resistance.
LincRNA-immunity landscape analysis identifies EPIC1 as a regulator of tumor immune evasion and immunotherapy resistance.
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长链非编码RNA（LincRNA）免疫全景分析确定EPIC1是肿瘤免疫逃逸和免疫治疗抗性的调节因子。
DOI：
10.1126/sciadv.abb3555
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发表时间：
2021-03
期刊：
影响因子：
13.6
通讯作者：
Yang D
中科院分区：
文献类型：
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作者：
Guo W;Wang Y;Yang M;Wang Z;Wang Y;Chaurasia S;Wu Z;Zhang M;Yadav GS;Rathod S;Concha-Benavente F;Fernandez C;Li S;Xie W;Ferris RL;Kammula US;Lu B;Yang D
EPIC1 - EZH2轴的激活成为肿瘤免疫逃逸和免疫治疗耐药的一个可靶向机制。
通过对32种癌症类型的9626个肿瘤样本中的长链非编码RNA（lincRNA）表达和肿瘤免疫反应进行综合分析，我们开发了一种基于lincRNA的免疫反应（LIMER）评分，它可以预测多种癌症类型中免疫细胞的浸润和患者的预后。我们的分析还确定了肿瘤特异性的lincRNAs，包括EPIC1，其可能调节多种癌症类型中的肿瘤免疫反应。具有免疫活性的小鼠模型和体外共培养实验表明，EPIC1通过抑制肿瘤细胞抗原呈递诱导肿瘤免疫逃逸和对免疫治疗的抵抗。从机制上讲，长链非编码RNA EPIC1与组蛋白甲基转移酶EZH2相互作用，导致IFNGR1、TAP1/2、ERAP1/2和MHC - I基因的表观遗传沉默。对EZH2进行基因和药物抑制可消除EPIC1的免疫相关致癌作用及其对干扰素 - γ信号通路的抑制。EPIC1 - EZH2轴成为肿瘤免疫逃逸的一种潜在机制，可作为免疫治疗的治疗靶点。
EPIC1-EZH2 axis activation emerges as a targetable mechanism for tumor immune evasion and immunotherapy resistance. Through an integrative analysis of the lincRNA expression and tumor immune response in 9,626 tumor samples across 32 cancer types, we developed a lincRNA-based immune response (LIMER) score that can predict the immune cells infiltration and patient prognosis in multiple cancer types. Our analysis also identified tumor-specific lincRNAs, including EPIC1, that potentially regulate tumor immune response in multiple cancer types. Immunocompetent mouse models and in vitro co-culture assays demonstrated that EPIC1 induces tumor immune evasion and resistance to immunotherapy by suppressing tumor cell antigen presentation. Mechanistically, lincRNA EPIC1 interacts with the histone methyltransferase EZH2, leading to the epigenetic silencing of IFNGR1, TAP1/2, ERAP1/2, and MHC-I genes. Genetic and pharmacological inhibition of EZH2 abolish EPIC1’s immune-related oncogenic effect and its suppression of interferon-γ signaling. The EPIC1-EZH2 axis emerges as a potential mechanism for tumor immune evasion that can serve as therapeutic targets for immunotherapy.
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影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
影响因子：
64.5
作者：
Basu A;Bodycombe NE;Cheah JH;Price EV;Liu K;Schaefer GI;Ebright RY;Stewart ML;Ito D;Wang S;Bracha AL;Liefeld T;Wawer M;Gilbert JC;Wilson AJ;Stransky N;Kryukov GV;Dancik V;Barretina J;Garraway LA;Hon CS;Munoz B;Bittker JA;Stockwell BR;Khabele D;Stern AM;Clemons PA;Shamji AF;Schreiber SL
通讯作者：
Schreiber SL
影响因子：
64.5
作者：
Gomez JA;Wapinski OL;Yang YW;Bureau JF;Gopinath S;Monack DM;Chang HY;Brahic M;Kirkegaard K
通讯作者：
Kirkegaard K
影响因子：
30.5
作者：
通讯作者：
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影响因子：
82.9
作者：
通讯作者：
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