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Dev Cell. 2019 Sep 9;50(5):658-671.e7. doi: 10.1016/j.devcel.2019.06.011. Epub 2019 Jul 18.

DUX4 Suppresses MHC Class I to Promote Cancer Immune Evasion and Resistance to Checkpoint Blockade.

Author information

1
Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
2
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
3
Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
4
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
5
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Neurology, University of Washington, Seattle, WA 98195, USA. Electronic address: stapscot@fredhutch.org.
6
Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: rbradley@fredhutch.org.

Abstract

Advances in cancer immunotherapies make it critical to identify genes that modulate antigen presentation and tumor-immune interactions. We report that DUX4, an early embryonic transcription factor that is normally silenced in somatic tissues, is re-expressed in diverse solid cancers. Both cis-acting inherited genetic variation and somatically acquired mutations in trans-acting repressors contribute to DUX4 re-expression in cancer. Although many DUX4 target genes encode self-antigens, DUX4-expressing cancers were paradoxically characterized by reduced markers of anti-tumor cytolytic activity and lower major histocompatibility complex (MHC) class I gene expression. We demonstrate that DUX4 expression blocks interferon-γ-mediated induction of MHC class I, implicating suppressed antigen presentation in DUX4-mediated immune evasion. Clinical data in metastatic melanoma confirmed that DUX4 expression was associated with significantly reduced progression-free and overall survival in response to anti-CTLA-4. Our results demonstrate that cancers can escape immune surveillance by reactivating a normal developmental pathway and identify a therapeutically relevant mechanism of cell-intrinsic immune evasion.

KEYWORDS:

DUX4; cancer; immune checkpoint blockade; immune evasion; immunotherapy

PMID:
31327741
PMCID:
PMC6736738
[Available on 2020-09-09]
DOI:
10.1016/j.devcel.2019.06.011

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