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KDM5A Inhibits Antitumor Immune Responses Through Downregulation of the Antigen-Presentation Pathway in Ovarian

Heng Liu1, Jianhuang Lin1, Wei Zhou1

  • 1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.

Cancer Immunology Research
|June 21, 2022
PubMed

Insights

Lysine-specific demethylase 5A (KDM5A) hinders CD8+ T cell infiltration in epithelial ovarian cancer (EOC), suppressing anti-tumor immunity. Inhibiting KDM5A may enhance immune responses against EOC.

Area of Science:

  • Immunology
  • Epigenetics
  • Oncology

Background:

  • CD8+ T cell infiltration into tumors is a key predictor of patient outcomes in epithelial ovarian cancer (EOC).
  • Tumor epigenetics can influence immune cell infiltration, impacting anti-tumor responses.
  • Lysine-specific demethylase 5A (KDM5A), an H3K4 demethylase, has been implicated in cancer but its role in immune infiltration is unclear.

Purpose of the Study:

  • To investigate the role of KDM5A in regulating immune cell infiltration and anti-tumor immunity in EOC.
  • To explore the mechanistic link between KDM5A and antigen processing and presentation pathways.
  • To evaluate the therapeutic potential of KDM5A inhibition in EOC.

Main Methods:

  • Assessed KDM5A's impact on immune cell infiltration and anti-tumor responses in EOC models.
  • Investigated KDM5A's effect on genes within the antigen processing and presentation pathway.
  • Utilized in vitro assays and a syngeneic EOC mouse model to study KDM5A inhibition.

Main Results:

  • KDM5A was found to impair immune cell infiltration and inhibit anti-tumor immune responses in EOC.
  • KDM5A was shown to silence genes critical for antigen processing and presentation.
  • KDM5A inhibition restored antigen presentation gene expression in vitro and enhanced CD8+ T cell-mediated anti-tumor immunity in vivo.
  • A negative correlation between KDM5A expression and HLA-A/HLA-B expression was observed across multiple cancer types.

Conclusions:

  • KDM5A acts as a significant regulator of CD8+ T cell infiltration into tumors.
  • KDM5A inhibition represents a potential novel therapeutic strategy to augment anti-tumor immune responses in EOC and other cancers.

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