The gene DUX4 usually stays dormant in normal tissues, but if it's activated, it can cause a type of muscular dystrophy. Now, a team at Fred Hutchinson Cancer Research Center has found that the mechanisms that activate DUX4 also help some cancer cells evade drugs that are designed to treat the disease by blocking immune checkpoints.
By screening 9,759 samples from 33 different cancer types, the team found that DUX4 is activated in many solid tumors of the bladder, breast, lung, kidney and stomach. Expression of the gene prevented immune cells from recognizing cancer cells, thereby promoting resistance to immuno-oncology agents, the team showed. They published the discoveries in the journal Development Cell.
DUX4 is usually expressed when an embryo forms and develops, as embryonic cells need to evade detection by the maternal immune system, the researchers explained in a statement. The gene is perhaps best known for causing facioscapulohumeral muscular dystrophy (FSHD), in which changes in the chromosome prevent DUX4 from being turned off in muscle cells.
Surprisingly, the Fred Hutchinson researchers noticed that many immune-cell-specific genes were tamped down in DUX4-expressing cancers. They showed that, in cancer, DUX4 re-expression is associated with reduced activities of CD8+ killer T cells and natural killer cells, both of which are vital players in the fight against tumor cells.
Moreover, DUX4 suppresses "MHC class 1 molecules," which normally help the immune system recognize cancer. Because checkpoint inhibitors rely on antigen presentation to work, the researchers hypothesized that DUX4 might promote resistance to these immune therapies.
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Biopsies from patients with metastatic melanoma showed those who didn’t respond well to drugs that inhibit the immune checkpoint CTLA-4 exhibited significantly higher levels of DUX4 than responsive patients did, the team reported. And clinical data confirmed that DUX4 expression was associated with significantly reduced progression-free and overall survival in response to anti-CTLA-4 treatment.
Cancer immunotherapies have been widely adopted, but some patients don’t respond to them. Exploring ways to improve these powerful cancer treatments has become a popular pursuit among oncology researchers. Columbia University scientists recently engineered a strain of Escherichia coli to deliver immunotherapy directly to solid tumors. And a collaboration between OnKure Therapeutics and the University of Colorado showed that adding an HDAC inhibitor to anti-PD-1 drugs could overcome resistance in mouse models with B-cell lymphoma.
The Fred Hutchinson team, led by Robert Bradley and Stephen Tapscott, suggests that cancer cells express DUX4 to avoid attack from the immune system. Therefore, they hope developing DUX4-targeted treatments might improve the success of immunotherapies.