The question of why immunotherapy eradicates cancer in some people while having little effect on the majority of patients has vexed scientists since the introduction of the treatment. Now, researchers at the Fred Hutchinson Cancer Research Center have identified a gene from the earliest stages of human development that helps cloak the disease from the most common immunotherapy methods.

The gene at the heart of the discovery is DUX4, which plays a role in the earliest stages of human embryonic development. Rarely seen in the cells of healthy adults, DUX4 is also activated in people with muscular dystrophy.

Doctors Robert Bradley and Stephen Tapscott mined the genetic profiles of 10,000 cancer samples in order to identify genes that were expressed by the cancer cells but not healthy tissues. For the data, the team relied on the Cancer Genome Atlas, a genomics project from the National Institute of Health.

“This study is an example of the unexpected things you can learn from large scale genomic data,” said Bradley.

Their analysis showed that patients whose cancers turned on the DUX4 gene were less likely to respond to treatment from checkpoint inhibitors, a class of immunotherapy drugs that enable the body’s immune system to attack cancer.

“DUX4 turns off the ability of the cell to show itself to the immune system,” said Tapscott, who previously studied the gene’s role in FSHD muscular dystrophy. DUX4 was found in the solid tumors of bladder, breast, lung, kidney and stomach cancers.

The study, published today in Developmental Cell, was co-authored by Tapscott and Bradley along with Fred Hutch postdoctoral fellow Guo-Liang Chew and staff scientist Amy Campbell.

The discovery of DUX4’s role could lead to the development of new cancer-fighting drugs that turn off the gene in order to make checkpoint inhibitors more effective. It also adds to our understanding of the early embryo.

“DUX4 is normally turned on in the very early embryo,” said Bradley. “This is a very special time because the embryo has foreign genetic material relative to the maternal tissue.” The researchers hypothesized that the same qualities that allow the gene to hide cancer may also protect the embryo from the mother’s immune system.