DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers - Research article

Sep 21, 2026

Uploaded by Eliana

Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. DUX4, an embryonic transcription factor, was previously linked to suppression of interferon-γ signaling and antigen presentation. This study reports DUX4 as a common feature of metastatic tumors, present in ~10–50% of advanced bladder, breast, kidney, prostate, and skin cancers, and associated with immune cell exclusion and decreased PD-L1 blockade response, as well as worse survival.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages26

Reading Time1 h 6 min

AccessFree to download

Abstract

Introduction

eLife digest

RESEARCH ARTICLE *For correspondence: [rbradley@fredhutch.org](rbradley@fredhutch.org)[ ](rbradley@fredhutch.org)Competing interest: See page 18 Funding: See page 18 Sent for Review 14 June 2023 Preprint posted 11 July 2023 Reviewed preprint posted 01 September 2023 Reviewed preprint revised 10 April 2024 Version of Record published 03 June 2024 Reviewing Editor: Mark Linch, University College London, United Kingdom Copyright Pineda and Bradley. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers Jose Mario Bello Pineda1,2,3,4, Robert K Bradley1,2,3* 1Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, United States; 2 Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, United States; 3 Department of Genome Sciences, University of Washington, Seattle, United States; 4 Medical Scientist Training Program, University of Washington, Seattle, United States | Abstract Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that DUX4 expression is a common feature of metastatic tumors, with ~10–50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing DUX4 . DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. DUX4 expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with DUX4 expression associated with a median reduction in survival of over 1 year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance. | | --- | | eLife assessment
This study presents a valuable finding on the association between DUX4 expression with features of immune evasion in human tissue and clinical outcomes in patients with advanced urothelial cancer. The evidence supporting the claims of the authors is convincing, using a range of corroborative statistical techniques. Compared to an earlier version, the quality of the manuscript has been enhanced, for example Figure 5 now illustrates the key features of survival probability estimates overtime for patients assigned to with the test or training set. | Introduction Immune checkpoint inhibition (ICI) therapy utilizes immunomodulatory monoclonal antibodies to stimulate patient anti-tumor immune responses. Blockade of T cell co-inhibitory receptors, such as CTLA-4 and the PD-1/PD-L1 axis, has achieved major success in the treatment of diverse metastatic cancers compared to first-line chemotherapy (Doki et al., 2022; Hellmann et al., 2019; Klein et al., 2020; Larkin et al., 2019; Motzer et al., 2020; Stein et al., 2022) . However, a majority of advanced cancer patients fail to respond to ICI due to de novo or acquired resistance, the mechanistic bases of which remain incompletely understood. Diverse mechanisms modulate sensitivity and resistance to ICI (Kalbasi and Ribas, 2020) . These mechanisms include defects in Major Histocompatibility Complex (MHC) class I-mediated antigen presentation due to loss of B2M or HLA (Grasso et al., 2018; Lee et al., 2020; McGranahan et al., Pineda and Bradley. eLife 2023;12:RP89017. DOI: [https://doi.org/10.7554/eLife.89017](https://doi.org/10.7554/eLife.89017) 1 of 26 Research article Cancer Biology | Genetics and Genomics eLife digest Over time cance

FAQs

What is the role of DUX4 in metastatic cancers according to this study?

DUX4 is presented as a common feature of metastatic tumors, associated with immune evasion characteristics linked to interferon-γ signaling and antigen presentation.

How is DUX4 expression related to response to PD-L1 blockade?

DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in urothelial carcinoma patients.

Does DUX4 expression predict survival independent of other factors?

Yes. DUX4 remains a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features, with an associated median survival reduction of over one year.

Sep 21, 2026

Uploaded by Eliana