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Epigenetic Induction of Cancer-Testis Antigens and Endogenous Retroviruses at Single-Cell Level Enhances Immune

Thomas J Lai1, Lu Sun1, Kevin Li1

  • 1Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.

Cancer Research Communications
|June 10, 2024
PubMed

Insights

Decitabine (DAC) treatment epigenetically primes glioblastoma (GBM) by inducing cancer-testis antigens (CTA) and enhancing T-cell responses. This approach reactivates human endogenous retroviruses and interferon signaling, improving targeted immunotherapies for glioma.

Area of Science:

  • Immunology
  • Epigenetics
  • Oncology

Background:

  • Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options.
  • Decitabine (DAC) has shown potential in inducing cancer-testis antigens (CTA) for adoptive T-cell therapy in GBM.
  • The precise mechanisms by which DAC enhances GBM immunogenicity require further investigation.

Purpose of the Study:

  • To elucidate the epigenetic and transcriptional mechanisms by which DAC enhances T-cell functionality in glioma.
  • To investigate the role of DNA methylation in regulating CTA expression in gliomas.
  • To assess the impact of DAC treatment on tumor-intrinsic factors like human endogenous retroviruses and interferon response.

Main Methods:

  • Analysis of CTA expression (e.g., NY-ESO-1) in patient tissue, immortalized glioma cells, and patient-derived gliomaspheres.
  • Assessment of DNA methylation patterns and their effect on CTA promoter regions.
  • Evaluation of T-cell responses, including cytokine profiles, upon targeting of DAC-induced antigens in glioma cells.
  • Investigation of DAC-induced changes in human endogenous retroviruses, interferon response signatures, and MHC-I expression.

Main Results:

  • Basal CTA expression in gliomas is suppressed by promoter hypermethylation.
  • DAC treatment inhibits DNA methylation, leading to the induction of CTA (e.g., NY-ESO-1) at a single-cell level.
  • DAC also reactivates tumor-intrinsic human endogenous retroviruses, interferon response signatures, and MHC-I.
  • Targeting of DAC-induced antigens by engineered T-cells promotes specific and polyfunctional T-cell cytokine profiles.

Conclusions:

  • DAC epigenetically primes gliomas by inducing targetable tumor antigens and enhancing T-cell functionality.
  • The study provides a mechanistic rationale for using DAC to improve targeted immune therapies in glioma.
  • DAC's ability to simultaneously induce antigens and boost anti-tumor immune responses offers a promising strategy for GBM treatment.

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