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Cancer Immunology, Immunotherapy
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Open Access 01-10-2024 | Pancreatic Cancer | Research

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

Authors: Yesiboli Tasiheng, Xuan Lin, Xu Wang, Xuan Zou, Yusheng Chen, Yu Yan, Mingjian Ma, Zhengjie Dai, Xu Wang, Xianjun Yu, He Cheng, Chen Liu

Published in: Cancer Immunology, Immunotherapy | Issue 10/2024

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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.
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Metadata
Title
DNA hypo-methylation and expression of GBP4 induces T cell exhaustion in pancreatic cancer
Authors
Yesiboli Tasiheng
Xuan Lin
Xu Wang
Xuan Zou
Yusheng Chen
Yu Yan
Mingjian Ma
Zhengjie Dai
Xu Wang
Xianjun Yu
He Cheng
Chen Liu
Publication date
01-10-2024
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 10/2024
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-024-03786-3

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