
DUX4 expression is a common feature of diverse metastatic cancers, where it suppresses anti-tumor immunity and is associated with decreased response and survival in patients treated with immune checkpoint inhibitors.


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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 one year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance.

### Competing Interest Statement

R.K.B. is an inventor on a patent application submitted by Fred Hutchinson Cancer Center that covers DUX4 expression in cancers and response to immunotherapy. R.K.B. is a founder and scientific advisor of Codify Therapeutics and Synthesize Bio and holds equity in both companies. R.K.B. has received research funding from Codify Therapeutics unrelated to the current work. The remaining authors declare no competing interests.

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

dux4-expression-is-prevalent-in-metastatic-cancers-and-predicts-poor-response-to-immune-checkpoint-inhibition


DUX4 Expression is Prevalent in Metastatic Cancers and Predicts Poor Response to Immune Checkpoint Inhibition
