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Immune Response Dampened in Many Cancers by Reactivation of Embryonic Gene

NEW YORK – Results from a pan-cancer gene expression analysis suggest that some tumors dodge checkpoint blockade immunotherapy by reactivating an embryonic transcription factor called DUX4, which is normally expressed during preimplantation to decrease maternal immune activity against the fetus but silenced in adult tissues.

"This study suggests that cancer cells express DUX4 to hijack a normal early developmental program that can suppress anti-cancer immune activity," co-senior and co-corresponding author Stephen Tapscott, a researcher at the Fred Hutchinson Cancer Research Center, said in a statement.

As they reported online today in Developmental Cell, Tapscott and colleagues from Fred Hutchinson and the University of Washington analyzed RNA sequence data from the Cancer Genome Atlas project for almost 9,800 tumor samples from dozens of cancer types, along with hundreds of matched tumor-adjacent samples and Illumina Body Map 2.0 data on 34 tissues from cancer-free individuals.

Together with Genotype-Tissue Expression (GTEx) project and Human Proteome Map data, the gene expression profiles revealed recurrent re-expression of DUX4 in breast, lung, stomach, and other solid tumor types, the team reported. The group's follow-up experiments suggested that this expression interferes with immune activity, blunting the effects of checkpoint inhibitor immunotherapies that are meant to unleash the immune system against tumors.

Prior studies have shown that DUX4 is re-expressed in individuals with facioscapulohumeral muscular dystrophy via epigenetic changes. In the case of cancer, the current results suggest that DUX4 re-expression can block major histocompatibility complex (MHC) class I antigen activation by the cytokine interferon gamma.

For their initial analyses, the researchers considered transcriptome profiles for nearly 9,800 tumor samples assessed for TCGA, along with transcriptome data for matched normal samples or samples from health volunteers, quantifying gene expression in the cancers compared to the unaffected somatic tissues.

Along with elevated expression of known cancer contributors, the team saw pan-cancer enrichment for DUX4 as well as the meiosis-specific cohesin subunit-coding gene SMC1B and the chorionic gonadotropin-coding gene CGB5.

"DUX4 was a particularly intriguing candidate for modulating tumor-immune interactions," the authors wrote, noting that the gene "is expressed at low levels in the immune-privileged sites of the testis and thymus but otherwise silenced in somatic tissues."

In their analyses, the researchers saw DUX4 expression in a dozen cancer types, with re-expression apparently arising via a mechanism that was distinct from that previously described in the skeletal muscle of individuals with FSHD.

The available gene expression signatures further suggested that cancers expressing DUX4 had lower-than-usual immune activity against the tumors, as well as muted expression of MHC class I genes, prompting the team to take a closer look at other features in available RNA sequence sets.

After demonstrating in cell line experiments that DUX4 expression could block interferon gamma-related MHC class I antigen presentation, the researchers focused in on RNA sequence data from 41 metastatic melanoma patients treated with anti-CTLA4 checkpoint immunotherapy and 27 patients treated with anti-PD-1.

The metastatic melanoma cases with enhanced expression of DUX4 had decreased treatment response, poorer progression-free survival, and reduced overall survival after anti-CTLA4 treatment, the team reported. Anti-PD-1 treatment response and overall survival also appeared to be somewhat worse in the DUX4-expressing metastatic melanoma cases, though those results did not reach statistical significance.

"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," the authors wrote, noting that "the physiological consequences of DUX4 expression in [FSHD muscle and cancer] disease states are quite different."