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Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity

Gabriel K Griffin1,2,3, Jingyi Wu1,2, Arvin Iracheta-Vellve1

  • 1Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Nature
|May 6, 2021
PubMed

Insights

The study identifies SETDB1 as a key epigenetic regulator that suppresses anti-tumor immunity. Loss of SETDB1 enhances cancer cells' sensitivity to immunotherapy by activating immune responses.

Area of Science:

  • Cancer Research
  • Epigenetics
  • Immunology

Background:

  • Epigenetic dysregulation is a hallmark of cancer, contributing to immune evasion.
  • Identifying factors that control cancer cell immune sensitivity is crucial for developing effective immunotherapies.

Purpose of the Study:

  • To identify epigenetic regulators modulating cancer cell immune sensitivity.
  • To investigate the role of SETDB1 in immune escape and resistance to immune checkpoint blockade.

Main Methods:

  • Conducted in vivo CRISPR-Cas9 screens in mouse tumor models treated with immune checkpoint blockade.
  • Targeted 936 chromatin regulators to identify factors influencing immune sensitivity.
  • Analyzed SETDB1 amplification in human tumors and its association with immune exclusion.

Main Results:

  • Identified SETDB1 (H3K9 methyltransferase) and associated complexes (HUSH, KAP1) as mediators of immune escape.
  • SETDB1 amplification in human tumors correlates with immune exclusion and resistance to immune checkpoint blockade.
  • SETDB1 loss derepresses transposable elements and immunostimulatory genes, triggering T cell responses.

Conclusions:

  • SETDB1 acts as an epigenetic checkpoint suppressing tumor-intrinsic immunogenicity.
  • SETDB1 is a potential therapeutic target for enhancing cancer immunotherapy outcomes.

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