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Getting back to your roots
SEATTLE—Some tumor cells survive and resist treatment by developing resistance to certain therapeutics, but others are doing so by getting back to basics—embryonic basics, in fact. A research team from Fred Hutchinson Cancer Research Center has discovered that tumor cells can manipulate the gene DUX4 to camouflage themselves from the immune system, and their results were published in Developmental Cell.
DUX4 is an embryonic gene that is activated after an egg is fertilized. It works to ensure the mother's immune system does not see the developing fetus as a foreign body, similar to how anti-rejection medication convinces a patient's immune system not to reject a transplanted organ. Additionally, according to a press release by Sabrina Richards of the Fred Hutch News Service, DUX4 is a transcription factor that is supposed to be permanently turned off in adult tissues. Beyond its role in embryonic development, this gene also leads to the inherited muscular disorder facioscapulohumeral muscular dystrophy (FSHD) when active in adult muscle cells.
Fred Hutchinson researcher Dr. Stephen Tapscott, an expert in DUX4 and co-leader of this research, has been examining the gene both within FSHD and in terms of cancer. As noted in Richards' piece, several of the DUX4 target genes are ones that are only activated during embryonic development, sperm development or cancer.
To further explore this connection, the authors noted in their paper that they “performed a pan-cancer analysis of tumor transcriptomes in order to identify potential regulators of tumor-immune interactions,” in search of genes that were expressed solely in cancer or “immune-privileged sites such as the testes and early embryo.” They found three genes with the strongest pan-cancer signals: DUX4, CGB5 and SMC1B.
“We therefore undertook an unbiased search for such genes using the transcriptomes of 9,759 samples from 33 distinct cancer types, 704 associated peritumoral normal samples, and 34 tissues from healthy individuals,” the authors continued. “Our analysis revealed that DUX4, an early embryonic transcription factor that is normally silenced in somatic tissues, is re-expressed in many solid cancer types. DUX4 re-expression in cancer results in suppression of MHC class I-dependent antigen presentation, immune evasion, and resistance to immune checkpoint blockade.”
The paper also reported that this gene is commonly expressed in “cancers of the bladder, breast, cervix, endometrium, esophagus, lung, ovary, kidney, soft tissue, and stomach, and particularly frequently expressed in testicular germ cell cancers and thymomas.”
The researchers found that turning on DUX4 provides a number of benefits for tumors in terms of evading the immune system. T cells target immune threats based on the peptides found in a cell's molecular histocompatibility complex (MHC) class I on the surface of the cell, and as Richards reported, “when the team looked at MHC-I levels in tumor cell lines, they found that high levels of DUX4 correlated with low levels of MHC.”
“DUX4 is preventing any peptide presentation, so the [cancer] cell is invisible to the immune system,” Tapscott explained.
DUX4 activity could also explain why many patients don't respond to checkpoint inhibitor drugs. When the scientists examined tissue samples from cancer patients who had undergone treatment with Yervoy (ipilimumab), they noted that the tumors of patients who didn't respond had noticeably higher DUX4 levels than those in patients who did respond. In addition, “patients with little to no DUX4 in their tumors survived longer than patients with DUX4-high tumors,” Richards reported.
“It’s very important to understand why some patients respond [to immunotherapy] and some don’t, both in order to be able to give patients advice on what medication would be most effective, and in order to try to design additional therapies that will let more patients respond to immunotherapy,” said Dr. Robert Bradley, a computational biologist at Fred Hutch and co-leader of this work.
The authors are quick to note that more research is needed regarding this discovery, both to see if evaluating DUX4 levels could have predictive potential regarding patient response to therapy, and to explain the differences between DUX4 expression in FSHD and cancer. The team is also exploring whether targeting DUX4 could boost response to checkpoint inhibitors, as per Richards' article.
“Sustained expression of DUX4 in skeletal muscle causes apoptosis (Eidahl et al., 2016, Kowaljow et al., 2007), in contrast to DUX4’s importance during early embryogenesis and apparent compatibility with many malignancies. Determining why early embryos and cancer cells can tolerate DUX4 expression, while muscle cells cannot, may give insight into possible mechanisms for treating FSHD. Another notable difference is the frequent presence of inflammation and lymphocytic infiltration in FSHD muscle (Arahata et al., 1995) versus reduced immune infiltration in DUX4+ cancers. As DUX4 suppresses MHC class I in both untransformed muscle cells and cancer cells (Figures 5D–5I and S5B–S5D), further work is required to determine why DUX4 expression results in immune attack in FSHD muscle but immune evasion in cancers,” the researchers remarked.