Tumors frequently subvert major histocompatibility complex 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.

肿瘤经常破坏主要组织相容性复合物 I 类 (MHC-I) 肽呈递以逃避 CD8 ⁺T 细胞免疫监视，尽管它是如何完成的并不总是很明确。为了确定控制抗原呈递的全球监管网络，我们对人类弥漫性大 B 细胞淋巴瘤 (DLBCL) 进行了全基因组筛查。这种方法揭示了几十个正负调节 MHC-I 细胞表面表达的基因。经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肿瘤特异性 MHC-I 调节，并且大多数原发性 DLBCL 肿瘤显示出多种调节因子的遗传改变。我们将 SUGT1 确立为 MHC-I 和 MHC-II 细胞表面表达的主要正调节因子。此外，对抗原呈递的两种负调节剂的药理抑制作用，EZH2 和胸苷酸合酶，增强 DLBCL MHC-I 呈递。这些和其他基因代表了在癌症、传染病和自身免疫中操纵 MHC-I 免疫监视的潜在目标。