Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas.
Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas.
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DOI：
10.1016/j.immuni.2020.11.002
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发表时间：
2021-01-12
期刊：
影响因子：
32.4
通讯作者：
Yewdell JW
中科院分区：
文献类型：
--
作者：
Dersh D;Phelan JD;Gumina ME;Wang B;Arbuckle JH;Holly J;Kishton RJ;Markowitz TE;Seedhom MO;Fridlyand N;Wright GW;Huang DW;Ceribelli M;Thomas CJ;Lack JB;Restifo NP;Kristie TM;Staudt LM;Yewdell JW
肿瘤经常破坏MHC I类（MHC-I）肽呈递以逃避CD 8 + T细胞免疫监视，尽管这是如何实现的并不总是明确的。为了确定控制抗原呈递的全球调控网络，我们在人类弥漫性大B细胞淋巴瘤（DLBCL）中进行了全基因组筛选。这种方法揭示了几十个基因，积极和消极地调节MHC-I细胞表面表达。经验证的基因聚集在多个途径中，包括细胞因子信号传导、mRNA加工、内体运输和蛋白质代谢。基因可以表现出淋巴瘤亚型或肿瘤特异性MHC-I调节，大多数原发性DLBCL肿瘤在多个调节因子中表现出遗传改变。我们确定SUGT 1是MHC-I和MHC-II细胞表面表达的主要正调节因子。此外，抗原呈递的两种负调节因子EZH 2和胸苷酸合酶的药理学抑制增强DLBCL MHC-I呈递。这些基因和其他基因代表了在癌症、感染性疾病和自身免疫中操纵MHC-I免疫监视的潜在靶点。MHC I类复合物为CD 8 + T细胞免疫监视提供了基础。Dersh等人使用全基因组筛选鉴定了调节人B细胞淋巴瘤中MHC-I表面表达的新基因。这使得能够发现增强肿瘤抗原呈递给T细胞的药物，并可能改善免疫疗法。
Tumors frequently subvert MHC class I (MHC-I) peptide presentation to evade CD8+ T cell immunosurveillance, though how this is accomplished is not always well-defined. To identify the global regulatory networks controlling antigen presentation, we employed genome-wide screening in human diffuse large B cell lymphomas (DLBCLs). This approach revealed dozens of genes that positively and negatively modulate MHC-I cell surface expression. Validated genes clustered in multiple pathways including cytokine signaling, mRNA processing, endosomal trafficking, and protein metabolism. Genes can exhibit lymphoma subtype- or tumor-specific MHC-I regulation, and a majority of primary DLBCL tumors displayed genetic alterations in multiple regulators. We established SUGT1 as a major positive regulator of both MHC-I and MHC-II cell surface expression. Further, pharmacological inhibition of two negative regulators of antigen presentation, EZH2 and thymidylate synthase, enhanced DLBCL MHC-I presentation. These and other genes represent potential targets for manipulating MHC-I immunosurveillance in cancers, infectious diseases, and autoimmunity. MHC class I complexes provide the basis for CD8+ T cell immunosurveillance. Using genome wide screens, Dersh et al. identify novel genes regulating MHC-I surface expression in human B cell lymphomas. This enabled discovery of drugs that enhance tumor antigen presentation to T cells and can potentially improve immunotherapies.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1073/pnas.1222342110
发表时间：
2013-02-26
影响因子：
11.1
作者：
Boyle, Louise H.;Hermann, Clemens;Trowsdale, John
通讯作者：
Trowsdale, John
影响因子：
8.8
作者：
ESTEBAN, F;CONCHA, A;GARRIDO, F
通讯作者：
GARRIDO, F
影响因子：
5.3
作者：
Gandin, Valentina;Gutierrez, Gustavo J.;Ronaic, Ze'ev A.
通讯作者：
Ronaic, Ze'ev A.
CRISPR-CAS9介导的基因失活的高度活性SGRNA的合理设计。
影响因子：
46.9
作者：
Doench, John G.;Hartenian, Ella;Graham, Daniel B.;Tothova, Zuzana;Hegde, Mudra;Smith, Ian;Sullender, Meagan;Ebert, Benjamin L.;Xavier, Ramnik J.;Root, David E.
通讯作者：
Root, David E.