Targeting the Atf7ip-Setdb1 Complex Augments Antitumor Immunity by Boosting Tumor Immunogenicity.
Targeting the Atf7ip-Setdb1 Complex Augments Antitumor Immunity by Boosting Tumor Immunogenicity.
复制标题
DOI：
10.1158/2326-6066.cir-21-0543
复制
发表时间：
2021-11
影响因子：
10.1
通讯作者：
Wong, Kwok-Kin
中科院分区：
文献类型：
--
作者：
Hu, Hai;Khodadadi-Jamayran, Alireza;Dolgalev, Igor;Cho, Hyunwoo;Badri, Sana;Chiriboga, Luis A.;Zeck, Briana;Gregorio, Miguel Lopez De Rodas;Dowling, Catriona M.;Labbe, Kristen;Deng, Jiehui;Chen, Ting;Zhang, Hua;Zappile, Paul;Chen, Ze;Ueberheide, Beatrix;Karatza, Angeliki;Han, Han;Ranieri, Michela;Tang, Sittinon;Jour, George;Osman, Iman;Sucker, Antje;Schadendorf, Dirk;Tsirigos, Aristotelis;Schalper, Kurt A.;Velcheti, Vamsidhar;Huang, Hsin-yi;Jin, Yujuan;Ji, Hongbin;Poirier, John T.;Li, Fei;Wong, Kwok-Kin
使用基于CRISPR的抑制筛选，作者将Atf 7ip和Setdb 1确定为肿瘤抗原表达和呈递的表观遗传调节因子。这些调节因子的遗传缺陷增强了抗肿瘤免疫力，提示了克服肿瘤免疫逃避的新的免疫策略。在了解肿瘤如何逃避免疫监视方面取得了实质性进展。然而，已经开发了一些对抗肿瘤免疫逃避的措施。肿瘤抗原表达的抑制是癌症用来逃避免疫系统检测和破坏的常见适应性机制。表观遗传修饰在免疫侵袭的各个方面发挥关键作用，包括调节肿瘤抗原表达。为了鉴定肿瘤抗原表达的表观遗传调节因子，我们建立了具有沉默抗原表达的免疫逃逸的可移植同基因肿瘤模型，并使用该系统作为CRISPR-Cas9抑制剂筛选编码表观遗传修饰物的基因的平台。我们发现，破坏编码染色质修饰剂激活转录因子7相互作用蛋白（Atf 7ip）或其相互作用伴侣SET结构域分叉组蛋白赖氨酸甲基转移酶1（Setdb 1）的基因在肿瘤细胞中恢复肿瘤抗原表达。这导致增强的肿瘤免疫原性伴随着升高的内源性逆转录病毒（ERV）抗原和mRNA内含子保留。ERV去抑制与强有力的I型干扰素应答和增加的T细胞浸润相关，导致缺乏完整Atf 7ip或Setdb 1的细胞排斥。ATF 7IP或SETDB 1表达与人类癌症中的抗原加工和呈递途径、干扰素信号传导、T细胞浸润和细胞毒性呈负相关。我们的研究结果为在癌症免疫治疗中靶向Atf 7ip或Setdb 1提供了理论基础。
Using a CRISPR-based suppressor screen, the authors identify Atf7ip and Setdb1 as epigenetic regulators of tumor antigen expression and presentation. Genetic deficiency in these regulators enhances antitumor immunity, suggesting a new immunotherapeutic strategy for overcoming tumor immune evasion. Substantial progress has been made in understanding how tumors escape immune surveillance. However, few measures to counteract tumor immune evasion have been developed. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR–Cas9 suppressor screen for genes encoding epigenetic modifiers. We found that disruption of the genes encoding either of the chromatin modifiers activating transcription factor 7–interacting protein (Atf7ip) or its interacting partner SET domain bifurcated histone lysine methyltransferase 1 (Setdb1) in tumor cells restored tumor antigen expression. This resulted in augmented tumor immunogenicity concomitant with elevated endogenous retroviral (ERV) antigens and mRNA intron retention. ERV disinhibition was associated with a robust type I interferon response and increased T-cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T-cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.