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Broad Researcher’s Find SETDB1 Helps Tumors Evade the Immune System

Broad Researcher’s Find SETDB1 Helps Tumors Evade the Immune System

Tumors adopt diverse strategies to evade immune detection, including overexpression of inhibitory checkpoints, inactivation of antigen presentation, and editing of neoantigens. 

A team of researchers at Broad Institute performed in vivo CRISPR–Cas9 screens targeting 936 chromatin regulators in mouse tumor models treated with immune checkpoint blockade. They identified the H3K9 methyltransferase SETDB1 as a mediator of immune evasion. We also found that SETDB1 (1q21.3) amplification in human tumors is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune clusters associated with segmental duplication events, a central mechanism of genome evolution. SETDB1 loss derepresses latent TE-derived regulatory factors, immunostimulatory genes, and TE-encoded retroviral antigens in these regions and triggers TE-specific cytotoxic T Cell responses in vivo. 

When the team blocked SETDB1 in mouse models of cancer, immune cells increased their cell-killing activity, and tumors shrunk when the scientists treated the animals with immune checkpoint inhibitors, making it a promising target for cancer drug development. Inhibiting SETDB1 could make immunotherapy more effective in more patients.

 

References

Griffin GK, Wu J, Iracheta-Vellve A, et al. Epigenetic silencing by SETDB1 suppresses tumour-intrinsic immunogenicity. Nature. Online May 5, 2021. DOI: 10.1038/s41586-021-03520-4

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