小柯机器人

美国国立卫生研究院Jonathan W. Yewdell、Devin Dersh等研究人员合作，利用全基因组筛选鉴定出调节MHC-I和MHC-II的谱系和肿瘤特异性基因。相关论文于2020年12月2日在线发表在《免疫》杂志上。

为了确定控制抗原呈递的全局调控网络，研究人员在人类弥漫性大B细胞淋巴瘤（DLBCL）中采用了全基因组筛选。该方法揭示了数十种正向和负向调节MHC-1细胞表面表达的基因。经过验证的基因聚集在多种途径中，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特定于肿瘤的MHC-1调控，大多数原发性DLBCL肿瘤在多种调控因子中均表现出遗传改变。

研究人员发现，SUGT1是MHC-I和MHC-II细胞表面表达的主要正向调节因子。此外，对抗原呈递的两个负调节因子EZH2和胸苷酸合酶的药理抑制作用增强了DLBCL MHC-1呈递。这些和其他基因是在癌症、传染病和自身免疫中操纵MHC-1免疫监视的潜在靶标。

据悉，肿瘤通常会破坏MHC-1肽呈递，从而逃避CD8⁺T细胞的免疫监视，尽管这种方法的实现方式并不总是很明确。

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

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