The diverse pancreatic tumor cell-intrinsic response to IFNγ is determined by epigenetic heterogeneity. (28th May 2023)

• Record Type: Journal Article
• Authors: Chen, Yueyue; Shen, Xuqing; Tang, Yingying; Weng, Yawen; Yang, Wenjuan; Liu, Mingzhu; Xu, Dapeng; Shi, Juanjuan; Yang, Xiaotong; Yu, Feier; Xu, Junyi; Zhang, Zhengyan; Lu, Ping; Sun, Yongwei; Xue, Jing; Niu, Ningning
• Is Part Of: Cancer letters. Volume 562(2023)
• Publication Date: 2023-05-28
• Subjects: Pancreatic ductal adenocarcinoma (PDAC) -- Epigenetic regulation -- Cellular heterogeneity -- IFNγ -- PD-L1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2023.216153
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: IFNγ signaling is mainly mediated through the activation of the canonical JAK-STAT signaling pathway, transcription factors, and epigenetic modifications. The activation of IFNγ signaling pathway may provide a novel option for tumor immunotherapy, but the outcomes remain controversial. In fact, recent studies suggest that the resistance to IFNγ-dependent immunotherapies is commonly derived from the tumor cell-intrinsic heterogeneity, the molecular mechanism of which remains elusive. Therefore, elucidating the tumor cell-intrinsic heterogeneity in response to IFNγ would be beneficial to improve the efficacy of immunotherapy. Here, we first delineated the epigenetic redistribution and transcriptome alteration in response to IFNγ stimulation, and demonstrated that ectopic gain of H3K4me3 and H3K27Ac at the promoter region mainly contributed to the enhancement of IFNγ-mediated transcriptional activity of interferon-stimulated genes (ISGs). Furthermore, we found that the cellular heterogeneity of PD-L1 expression in response to IFNγ was mainly attributed to cell-intrinsic H3K27me3 levels. Enhancement of H3K27me3 by GSK-J4 limited PD-L1 hi tumor growth by salvaging the intratumoral cytotoxicity of CD8 + T cells, which may provide therapeutic strategies to overcome immune escape and resistance to IFNγ-based immunotherapies in pancreatic cancer. Highlights: The epigenetic gain of H3K4me3 and H3K27Ac mainly contributed to the fully activation of IFNγ-mediated transcription. The cellular heterogeneity of PD-L1 upon IFNγ stimulation was mainly determined by the diverse H3K27me3 deposition. GSK-J4 limited the immune evasion and tumor growth of PD-L1 hi subpopulation pancreatic tumor cell. Our work provided therapeutic strategies to overcome the resistance to IFNγ-based therapies in PDAC.