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A Murine Cell Line Based Model of Chronic CDK9 Inhibition to Study Widespread Non-Genetic Transcriptional Elongation Defects TEdeff in Cancers
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A Murine Cell Line Based Model of Chronic CDK9 Inhibition to Study Widespread Non-Genetic Transcriptional Elongation Defects TEdeff in Cancers

Published on: September 26, 2019

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Defective transcription elongation in a subset of cancers confers immunotherapy resistance

Vishnu Modur1, Navneet Singh1, Vakul Mohanty2

  • 1Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, 45229, OH, USA.

Nature Communications
|October 25, 2018
PubMed

Insights

Global defects in mRNA transcription elongation (TE) are common in cancers. These defects, termed transcription elongation defects (TEdeff), impair anti-tumor immunity and predict poor immunotherapy outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Global transcriptional dysregulation in cancer remains poorly understood.
  • mRNA transcription elongation (TE) defects are increasingly recognized in various cancers.

Purpose of the Study:

  • To investigate the role and impact of widespread transcription elongation defects (TEdeff) in cancer.
  • To determine the association of TEdeff with clinical outcomes, particularly in response to immunotherapy.

Main Methods:

  • Analysis of transcriptional profiles in a large cohort of cancers.
  • Characterization of gene expression patterns and signaling pathways in cancers with TEdeff.
  • In vivo studies involving pharmacologic or genetic induction of TEdeff in tumor models.

Main Results:

  • A significant proportion of cancers exhibit widespread TE defects (TEdeff).
  • TEdeff is associated with impaired mRNA processing of specific gene types and suppressed pro-inflammatory signaling.
  • TEdeff correlates with poor response and outcomes in patients undergoing immunotherapy for renal cell carcinoma and melanoma.
  • Induced TEdeff confers resistance to anti-tumor immunity and checkpoint inhibitor therapy.

Conclusions:

  • Defective transcription elongation is a novel mechanism of tumor immune evasion.
  • TEdeff represents a potential biomarker for predicting immunotherapy response.
  • Assessment of TEdeff in cancer patients may guide treatment decisions, especially for immunotherapy.

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