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SIN3B Loss Heats up Cold Tumor Microenvironment to Boost Immunotherapy in Pancreatic Cancer

Zhengyan Zhang1, Yingying Tang1, Yu Wang2

  • 1State Key Laboratory of Systems Medicine for Cancer, Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|September 24, 2024
PubMed

Insights

Targeting the epigenetic factor Sin3B in pancreatic cancer (PDAC) can enhance anti-tumor immunity. Sin3B loss boosts CD8+ T cell infiltration and sensitivity to immunotherapy, offering new therapeutic strategies for PDAC.

Area of Science:

  • Oncology
  • Immunology
  • Epigenetics

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) shows poor response to immunotherapy due to an immunosuppressive tumor microenvironment (TME).
  • Limited infiltration of CD8+ T cells is a key factor in PDAC's resistance to cancer treatments.
  • The role of epigenetic factors in shaping the PDAC TME is not fully understood.

Purpose of the Study:

  • To investigate the role of the epigenetic factor Sin3B in the PDAC tumor microenvironment.
  • To determine if modulating Sin3B affects anti-tumor immunity and immunotherapy response in PDAC.
  • To explore the mechanisms by which Sin3B influences the PDAC TME and immune cell infiltration.

Main Methods:

  • Utilized murine PDAC models to study the effects of Sin3B loss on the TME.
  • Analyzed gene expression, cytokine secretion (CXCL9/10), and epigenetic modifications (H3K27Ac) in Sin3B-deficient PDAC cells.
  • Correlated Sin3B expression with CD8+ T cell infiltration and CXCL9/10 levels in human PDAC samples.
  • Assessed the impact of Sin3B modulation on sensitivity to anti-PD1 therapy.

Main Results:

  • Loss of Sin3B in PDAC cells reshaped the TME, increasing CD8+ T cell infiltration and cytotoxicity.
  • Sin3B-deficient cells showed enhanced CXCL9/10 secretion upon Interferon-gamma (IFNγ) stimulation, amplifying the anti-tumor immune response via the CXCL9/10-CXCR3 axis.
  • Sin3B loss led to epigenetic changes, including increased H3K27Ac on immune response genes in PDAC cells.
  • Human PDAC samples exhibited an inverse correlation between SIN3B levels and CD8+ T cell infiltration and CXCL9/10 expression.
  • Lower SIN3B expression in PDAC patients correlated with better response to anti-PD1 therapy.

Conclusions:

  • Sin3B acts as a key epigenetic regulator in the PDAC TME, suppressing anti-tumor immunity.
  • Targeting Sin3B can enhance cytotoxic T cell infiltration and improve immunotherapy efficacy in PDAC.
  • Sin3B represents a potential therapeutic target or biomarker for enhancing immunotherapy in pancreatic cancer.
Keywords:
CD8+ T cell infiltrationCXCL9/10‐CXCR3 axisSin3Banti‐PD1 treatmentpancreatic ductal adenocarcinomatumor microenvironment

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