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Updated: Aug 4, 2025
Generation of Orthotopic Pancreatic Tumors and Ex vivo Characterization of Tumor-Infiltrating T Cell Cytotoxicity
Published on: December 7, 2019
The diverse pancreatic tumor cell-intrinsic response to IFNγ is determined by epigenetic heterogeneity
Yueyue Chen1, Xuqing Shen1, Yingying Tang1
1State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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.
Insights
Interferon gamma (IFNγ) resistance in cancer immunotherapy stems from tumor cell differences. Enhancing H3K27me3 epigenetic marks can overcome this resistance by boosting CD8+ T cell activity.
Area of Science:
- Immunology
- Epigenetics
- Cancer Biology
Background:
- Interferon gamma (IFNγ) signaling, primarily via the JAK-STAT pathway, is crucial for anti-tumor immunity but its therapeutic efficacy is debated.
- Tumor cell-intrinsic heterogeneity is a key factor in resistance to IFNγ-dependent immunotherapies, with underlying molecular mechanisms poorly understood.
- Understanding IFNγ response heterogeneity is vital for improving cancer immunotherapy outcomes.
Purpose of the Study:
- To investigate the epigenetic and transcriptomic alterations in response to IFNγ stimulation.
- To elucidate the mechanisms driving tumor cell heterogeneity in response to IFNγ, particularly PD-L1 expression.
- To explore therapeutic strategies targeting epigenetic modifications to overcome IFNγ resistance in pancreatic cancer.
Main Methods:
- Analysis of epigenetic redistribution (H3K4me3, H3K27Ac, H3K27me3) and transcriptome alterations upon IFNγ stimulation.
- Investigation of the role of H3K27me3 levels in regulating PD-L1 heterogeneity.
- Utilizing GSK-J4, an H3K27me3 enhancer, to assess its impact on tumor growth and CD8+ T cell activity.
Main Results:
- Ectopic gain of H3K4me3 and H3K27Ac at promoter regions enhanced IFNγ-mediated transcriptional activity of interferon-stimulated genes (ISGs).
- Cell-intrinsic H3K27me3 levels were identified as the primary driver of heterogeneous PD-L1 expression following IFNγ stimulation.
- Enhancement of H3K27me3 using GSK-J4 suppressed PD-L1-high tumor growth by restoring intratumoral CD8+ T cell cytotoxicity.
Conclusions:
- Epigenetic modifications, including H3K4me3 and H3K27Ac gains, significantly influence IFNγ-driven gene expression.
- H3K27me3 levels are critical determinants of PD-L1 heterogeneity and subsequent immune evasion in response to IFNγ.
- Targeting H3K27me3 with agents like GSK-J4 presents a promising strategy to overcome immune escape and enhance IFNγ-based immunotherapies in pancreatic cancer.
