DNA hypo-methylation and expression of GBP4 induces T cell exhaustion in pancreatic cancer.

IF 4.6 2区 医学 Q2 IMMUNOLOGY
Yesiboli Tasiheng, Xuan Lin, Xu Wang, Xuan Zou, Yusheng Chen, Yu Yan, Mingjian Ma, Zhengjie Dai, Xu Wang, Xianjun Yu, He Cheng, Chen Liu
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Abstract

Immunotherapy for pancreatic ductal carcinoma (PDAC) remains disappointing due to the repressive tumor microenvironment and T cell exhaustion, in which the roles of interferon-stimulated genes were largely unknown. Here, we focused on a typical interferon-stimulated gene, GBP4, and investigated its potential diagnostic and therapeutic value in pancreatic cancer. Expression analysis on both local samples and public databases indicated that GBP4 was one of the most dominant GBP family members present in the PDAC microenvironment, and the expression level of GBP4 was negatively associated with patient survival. We then identified DNA hypo-methylation in regulatory regions of GBP4 in PDAC, and validated its regulatory role on GBP4 expression via performing targeted methylation using dCas9-SunTag-DNMAT3A-sgRNA-targeted methylation system on selected DNA locus. After that, we investigated the downstream functions of GBP4, and chemotaxis assays indicated that GBP4 overexpression significantly improved the infiltration of CD8+T cells, but also induced upregulation of immune checkpoint genes and T cell exhaustion. Lastly, in vitro T cell killing assays using primary organoids suggested that the PDAC samples with high level of GBP4 expression displayed significantly higher sensitivity to anti-PD-1 treatment. Taken together, our studies revealed the expression patterns and epigenetic regulatory mechanisms of GBP4 in pancreatic cancer and clarified the effects of GBP4 on T cell exhaustion and antitumor immunology.

Abstract Image

DNA 低甲基化和 GBP4 的表达可诱导胰腺癌 T 细胞衰竭。
胰腺导管癌(PDAC)的免疫疗法由于肿瘤微环境的抑制和T细胞的衰竭而仍然令人失望,其中干扰素刺激基因的作用在很大程度上是未知的。在此,我们聚焦于一个典型的干扰素刺激基因--GBP4,研究其在胰腺癌中的潜在诊断和治疗价值。对本地样本和公共数据库进行的表达分析表明,GBP4是PDAC微环境中最主要的GBP家族成员之一,而且GBP4的表达水平与患者生存期呈负相关。随后,我们发现了PDAC中GBP4调控区的DNA低甲基化,并通过使用dCas9-SunTag-DNMAT3A-sgRNA靶向甲基化系统对选定的DNA位点进行靶向甲基化,验证了其对GBP4表达的调控作用。随后,我们研究了 GBP4 的下游功能,趋化实验表明,GBP4 的过表达能显著改善 CD8+T 细胞的浸润,同时还能诱导免疫检查点基因的上调和 T 细胞衰竭。最后,利用原代器官组织进行的体外T细胞杀伤试验表明,GBP4高表达的PDAC样本对抗PD-1治疗的敏感性明显更高。综上所述,我们的研究揭示了GBP4在胰腺癌中的表达模式和表观遗传调控机制,并阐明了GBP4对T细胞衰竭和抗肿瘤免疫学的影响。
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来源期刊
CiteScore
10.50
自引率
1.70%
发文量
207
审稿时长
1 months
期刊介绍: Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.
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