全基因組篩選鑑定出調節MHC-I和MHC-II的譜系和腫瘤特異性基因
作者：
小柯機器人發布時間：2020/12/4 13:10:01
美國國立衛生研究院Jonathan W. Yewdell、Devin Dersh等研究人員合作，利用全基因組篩選鑑定出調節MHC-I和MHC-II的譜系和腫瘤特異性基因。相關論文於2020年12月2日在線發表在《免疫》雜誌上。
為了確定控制抗原呈遞的全局調控網絡，研究人員在人類瀰漫性大B細胞淋巴瘤（DLBCL）中採用了全基因組篩選。該方法揭示了數十種正向和負向調節MHC-1細胞表面表達的基因。經過驗證的基因聚集在多種途徑中，包括細胞因子信號傳導、mRNA加工、內體運輸和蛋白質代謝。基因可以表現出淋巴瘤亞型或特定於腫瘤的MHC-1調控，大多數原發性DLBCL腫瘤在多種調控因子中均表現出遺傳改變。
研究人員發現，SUGT1是MHC-I和MHC-II細胞表面表達的主要正向調節因子。此外，對抗原呈遞的兩個負調節因子EZH2和胸苷酸合酶的藥理抑制作用增強了DLBCL MHC-1呈遞。這些和其他基因是在癌症、傳染病和自身免疫中操縱MHC-1免疫監視的潛在靶標。
據悉，腫瘤通常會破壞MHC-1肽呈遞，從而逃避CD8+T細胞的免疫監視，儘管這種方法的實現方式並不總是很明確。
附：英文原文
Title: Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas
Author: Devin Dersh, James D. Phelan, Megan E. Gumina, Boya Wang, Jesse H. Arbuckle, Jaroslav Holly, Rigel J. Kishton, Tovah E. Markowitz, Mina O. Seedhom, Nathan Fridlyand, George W. Wright, Da Wei Huang, Michele Ceribelli, Craig J. Thomas, Justin B. Lack, Nicholas P. Restifo, Thomas M. Kristie, Louis M. Staudt, Jonathan W. Yewdell
Issue&Volume: 2020-12-02
Abstract: Tumors frequently subvert major histocompatibility complex class I (MHC-I) peptidepresentation 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 employedgenome-wide screening in human diffuse large B cell lymphomas (DLBCLs). This approachrevealed dozens of genes that positively and negatively modulate MHC-I cell surfaceexpression. Validated genes clustered in multiple pathways including cytokine signaling,mRNA processing, endosomal trafficking, and protein metabolism. Genes can exhibitlymphoma subtype- or tumor-specific MHC-I regulation, and a majority of primary DLBCLtumors displayed genetic alterations in multiple regulators. We established SUGT1as a major positive regulator of both MHC-I and MHC-II cell surface expression. Further,pharmacological inhibition of two negative regulators of antigen presentation, EZH2and thymidylate synthase, enhanced DLBCL MHC-I presentation. These and other genesrepresent potential targets for manipulating MHC-I immunosurveillance in cancers,infectious diseases, and autoimmunity.
DOI: 10.1016/j.immuni.2020.11.002
Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30467-2