Nature Medicine | Spoonful of Medicine

Surprising epigenetic switch for ‘natural killer’ cells eyed for cancer therapy

NKcellsNatural killer cells are the instant assassins of the immune system with the ability to destroy foreign invaders and cancer cells at first sight. Although scientists have been studying how to harness the lethal abilities of these cells for more than three decades, little has been known about how these ‘NK’ cells develop from unspecialized immune cells. Now, researchers have discovered an enzyme that uses an epigenetic pathway—a process that modifies the way a cell’s DNA is read without actually changing the genetic blueprint itself—to boost the growth and function of NK cells.

NK cells could be a boon to cancer immunotherapy. These immune system soldiers are on constant surveillance duty, so it’s thought that they could eliminate the stray tumor cells that often elude chemotherapy. More than two dozen clinical trials to enhance NK activity against cancer are currently underway.

However, none of these drugs in development takes an epigenetic approach. That might be a mistake, in light of a study published today in the Proceedings of the National Academy of Sciences. A team of scientists led by Si-Yi Chen, an immunologist from the University of Southern California’s Norris Comprehensive Cancer Center in Los Angeles, shows that the enzyme MYSM1 (which stands for Myb-like, SWIRM and MPN domain-containing protein 1) controls the final steps of NK cell maturation through epigenetic changes. They suggest that increasing levels of this enzyme could help fight cancer by boosting the numbers of mature NK cells on patrol.

“It’s a very important contribution to our understanding of NK cell development,” says Porunelloor Mathew, a cancer immunologist at the University of North Texas Health Science Center in Fort Worth, who was not involved in the study.

All wound up

MYSM1 binds to histones, the proteins that create a spool around which our DNA is coiled, and induces a structural shift that exposes select genes to get read out and used. In previous work, Chen and his colleagues found that MYSM1 was essential in the early development of the immune systems’ B cells.

To pinpoint how MYSM1 might influence the growth of NK cells, the scientists made use of the surface markers specific to each stage of these cells’ development to count the amounts of NK cells at various points in the maturation process in the bone marrow, spleen and blood of six normal mice. When they compared those cell counts with those found in six mice specifically bred to lack MYSM1, they found the MYSM1-deficient mice had no mature NK cells. Yet, when scientists exposed immature NK cells taken from these MYSM1-deficient mice to a viral vector carrying the enzyme, the cells went on to develop into mature NKs cells.

To learn more about how MYSM1 exerted its effects, the researchers used labeling techniques to determine where the enzyme was typically found on strands of DNA. Interestingly, MYSM1 associated most with Id2, a gene known for making transcription factors that allow cell growth to continue. Furthermore, the enzyme was frequently located in the company of NFIL3, a protein that activates transcription at Id2. This work suggests that MYSM1 controls the final stages of NK maturation by recruiting proteins needed to activate factors that enable more development.

“This is still basic science research,” says Chen. “But we’ve seen that overexpressing MYSM1 can make the NK cells stronger. Still, we don’t know if human NK cells will behave the same.”

Further research should also help shed light on the utility of enhancing NK cell maturation to treat tumors. “From a cancer therapy point of view, this new research would enhance the NK immune response system overall,” says Mathew. “Whether that can be used to target specific cancers is the question.”

Image by Sebastian Kaulitzki via Shutterstock.com

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