Recent research by doctors at the Yale School of Medicine and the University of Massachusetts Medical School highlights a new method to fight cancer. The researchers studied a type of white blood cell called a natural killer cell. Normally, these cells inhibit the initiation of tumors, but the researchers investigated a cancer in which inhibition by natural killers did not occur — namely, hepatocellular carcinoma, a deadly form of liver cancer.

The study, which took place in Yale’s pathology department, began in March 2016 and took nearly two years to complete. It was published March 26 in the Proceedings of the National Academy of Sciences journal.

“Hepatocellular carcinoma is the second-most lethal form of cancer with less than 10 percent five-year survival rate,” said Suresh Bugide, the first author of the study and postdoctoral researcher at the medical school. “Current therapies only provide marginal clinical benefits.”

But the researchers hoped that natural killer cells could provide a possible solution. In hepatocellular carcinoma cells, they found, natural killer cells are not expressed because a key molecule associated with them is repressed. As a result, the natural killer cells do not do their job in eradicating cancer.

“Successful tumors that actually grow have strategies for either evading or blocking immune response,” explained Paula Kavathas, professor of laboratory medicine and immunobiology at the medical school.

The researchers then turned to epigenetics — the study of how genes are expressed — to find a way around the tumor cell’s defense mechanism, testing 32 chemicals to find one that could re-express the molecule of interest and reactivate the natural killer cells. They found that the chemical that worked did so by inhibiting a small enzyme called EZH2.

Because of this, the researchers were able to conclude that EZH2 deactivates natural killer cells. The team members then tested what happened when they inhibited EZH2 and found that doing so enhanced the natural killer cells’ ability to eradicate cancerous cells.

Kavathas, who was not involved in the study, said that exploring new treatment options based on these findings is “a reasonable approach to improving cancer therapy.”

Sandy Chang ’88, associate dean of science education at Yale College, agreed. He said the discovery of small molecules that can inhibit EZH2 is an exciting development and could potentially be used in clinical trials designed to combat hepatocellular carcinoma.

“Any treatment for hepatocellular carcinoma, especially those based on harnessing natural killer cells from one’s own immune system, is promising,” he said.

But Chang, who is also a professor of laboratory medicine at the medical school, said that the main drawback of the study was that it was conducted completely in vitro, as opposed to in a living animal model.

Chang said it would be “even more exciting” if inhibition of EZH2 using small molecules could prolong the lifespans of mice with hepatocellular carcinoma. Kavathas noted that sometimes methods that work in a cultured cell also work in vivo, and other times they don’t.

EZH2 inhibitors are already in clinical trials for lymphoma and sarcoma. But Bugide said he also hopes his study will inform and lead to more testing of EZH2’s use in cancer immune therapies.

“We want [to] further study the role of EZH2 inhibitors in enhancing immune function against cancer cells and also want to test these in in vivo mice models,” he said.

Each year in the United States, 22,000 men and 9,000 women are diagnosed with liver cancer, according to the Centers for Disease Control and Prevention.

Meera Rothman | meera.rothman@yale.edu