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Epigenetic Modulation of the Tumor Immune Microenvironment to Potentiate Immune Checkpoint Blockade Therapy

Johannes Menzel1, Joshua C Black2

  • 1Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Cancer Discovery
|February 7, 2020
PubMed

Insights

Immune checkpoint blockade (ICB) is ineffective in KRAS-mutant lung cancer. A new study identifies Asf1a as a key suppressor of ICB response by inhibiting GM-CSF, offering a potential therapeutic target.

Area of Science:

  • Oncology
  • Immunotherapy
  • Molecular Biology

Background:

  • Response rates to immune checkpoint blockade (ICB) are low in KRAS-mutant lung adenocarcinoma.
  • The tumor immune microenvironment plays a critical role in ICB efficacy.

Purpose of the Study:

  • To identify epigenetic regulators within the tumor microenvironment that influence ICB response.
  • To uncover novel therapeutic targets for improving ICB in KRAS-mutant lung cancer.

Main Methods:

  • Conducted an in vivo CRISPR screen of epigenetic regulators.
  • Focused on the tumor immune microenvironment in KRAS-mutant lung adenocarcinoma models.
  • Assessed the impact of identified regulators on ICB response and GM-CSF expression.

Main Results:

  • Identified Asf1a as a tumor-intrinsic suppressor of ICB.
  • Demonstrated that Asf1a suppresses ICB by inhibiting granulocyte-macrophage colony-stimulating factor (GM-CSF) expression.
  • Asf1a's role was uncovered through a comprehensive in vivo CRISPR screen.

Conclusions:

  • Asf1a is a novel tumor-intrinsic factor that negatively regulates ICB efficacy in KRAS-mutant lung adenocarcinoma.
  • Targeting Asf1a or enhancing GM-CSF expression may improve responses to ICB in this patient population.

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