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Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress

Wuchang Zhang1, Wei Liu1, Lingfei Jia1

  • 1Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Molecular Cell
|March 20, 2021
PubMed

Insights

Targeting KDM4A in squamous cell carcinoma (SCC) activates the intrinsic immune response and DNA replication stress. This approach enhances PD-1 blockade immunotherapy by eliminating cancer stem cells.

Area of Science:

  • Oncology
  • Immunology
  • Epigenetics

Background:

  • Histone H3 lysine 9 trimethylation (H3K9me3) demethylase KDM4A is crucial for squamous cell carcinoma (SCC) progression.
  • Activating tumor-cell-intrinsic immunity is key for effective cancer immunotherapy.

Purpose of the Study:

  • To investigate the role of KDM4A inhibition in promoting antitumor immunity in SCC.
  • To explore the mechanistic link between KDM4A inhibition, DNA replication stress, and immune activation.
  • To evaluate the synergistic effect of KDM4A inhibition and PD-1 blockade in SCC treatment.

Main Methods:

  • Inhibition of KDM4A in SCC models.
  • Analysis of heterochromatin compaction and DNA replication stress.
  • Assessment of cGAS-STING signaling pathway activation.
  • Evaluation of CD8+ T cell recruitment and activation.
  • In vivo lineage tracing studies.

Main Results:

  • KDM4A inhibition led to heterochromatin compaction and induced DNA replication stress in SCC cells.
  • This stress activated the intrinsic cGAS-STING immune signaling pathway via cytosolic DNA accumulation.
  • Combined KDM4A inhibition and PD-1 blockade suppressed SCC growth and metastasis.
  • The combination therapy effectively eliminated cancer stem cells in vivo.
  • KDM4A inhibition enhanced CD8+ T cell responses.

Conclusions:

  • Targeting KDM4A is a viable strategy to activate antitumor immunity in SCC.
  • KDM4A inhibition potentiates PD-1 blockade immunotherapy by exacerbating replication stress.
  • This dual approach offers a promising therapeutic avenue for SCC by targeting cancer stem cells and enhancing immune response.
Keywords:
DNA replication stressH3K9me3KDM4APD-1 blockadePhase separationcancer stem cellshead and neck squamous cell carcinomaheterochromatin condensatesimmune surveillancemetastasis

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