1. Academic Validation
  2. The diverse pancreatic tumor cell-intrinsic response to IFNγ is determined by epigenetic heterogeneity

The diverse pancreatic tumor cell-intrinsic response to IFNγ is determined by epigenetic heterogeneity

  • Cancer Lett. 2023 Apr 4;216153. doi: 10.1016/j.canlet.2023.216153.
Yueyue Chen 1 Xuqing Shen 1 Yingying Tang 1 Yawen Weng 1 Wenjuan Yang 1 Mingzhu Liu 1 Dapeng Xu 1 Juanjuan Shi 1 Xiaotong Yang 1 Feier Yu 1 Junyi Xu 1 Zhengyan Zhang 1 Ping Lu 1 Yongwei Sun 2 Jing Xue 3 Ningning Niu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: jingxue@sjtu.edu.cn.
  • 4 State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: niuningning@shsmu.edu.cn.
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-L1hi 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.

Keywords

Cellular heterogeneity; Epigenetic regulation; IFNγ; PD-L1; Pancreatic ductal adenocarcinoma (PDAC).

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