Immunotherapy—using the body’s immune system to attack cancer cells—has become a powerful cancer-fighting tool. But, for reasons that are unclear, tumours evade immune cells, making them resistant to these therapies.

Now a new study by Fox Chase Cancer Center scientists shows how a process called DNA methylation can regulate the immune response in colorectal cancer, laying the groundwork for potential new treatments. DNA methylation and demethylation is a balanced process that regulates gene expression. Methylation suppresses genes and essentially turns them off, while demethylation activates them again.

“By blocking this demethylation pathway, we can make these cancer cells very sensitive to killing by natural killer cells, which are immune cells,” said Alfonso Bellacosa, MD, PhD, the study’s lead author and a professor in the Nuclear Dynamics and Cancer research programme and a member of the Cancer Epigenetics Institute at Fox Chase. The study’s first author is Rossella Tricarico, PhD, a former research associate in Bellacosa’s lab, who is now an assistant professor in human and cancer genetics in the Department of Biology and Biotechnology at the University of Pavia in Italy.

Methylation was already known to play an important role in a wide variety of cancer types, including colon cancer. But exactly what role it played, and how it worked at the molecular level, was not understood. For the study, researchers wanted to understand the mechanism in detail and investigate how it could be exploited for better diagnosis and treatment.

First, they looked at colon tumours from mice that were missing enzymes that trigger demethylation. These tumours had higher levels of methylation throughout the genome, but especially in regions called CpG islands, clusters of genes that may regulate immune response.

When they analysed these “CIMP” tumours (short for CpG island methylator phenotype), they found that they showed more signs of inflammation and interferon response. These processes play a key role in the immune system’s ability to identify and attack disease cells. 

“When that happens, the tumours are more visible and better detected by the immune system,” Bellacosa said. “So the immune cells are able to come and infiltrate the tumours.”

Researchers then examined a human cancer database to look for colon tumours that were genetically similar to the CIMP mouse tumours. “We found again that these tumours were the ones with the highest methylation, and they also had the highest inflammation,” Bellacosa said.

Interestingly, the tumours not only had lower levels of an enzyme that demethylates DNA, but they also had higher levels of an enzyme that promotes methylation, he added.

“The key finding, in both the mouse and human models, is that high levels of DNA methylation correlate with high levels of inflammatory and interferon response,” he said. “This is independent of the pathways we currently associate with an inflammatory response in colon cancer and represents a completely new and unexpected finding.”

In the final phase of the experiments, researchers exposed colon cancer cells to “killer” immune cells. By blocking the genes that trigger demethylation, they made the cancer cells much more vulnerable to killing by the immune cells. “This provides a potential new way of rendering tumour cells more sensitive to immunotherapy,” he said.

While the study looked at colon cancer cells, Bellacosa noted that the findings could have implications for a wide variety of cancers, including melanoma and lung cancer. Next, the researchers will work to better understand the molecular mechanism through which methylation activates the inflammatory and interferon response, Bellacosa said.

“We are also actively looking for inhibitors,” he added, “drugs that could inhibit this pathway and will then be the first step toward creating new epigenetic therapies that will increase sensitisation to immunotherapy.”

The study, “TET1 and TDG Suppress Inflammatory Response in Intestinal Tumorigenesis: Implications for Colorectal Tumors With the CpG Island Methylator Phenotype,” was published in Gastroenterology.

Source: Fox Chase Cancer Center