It's become clear that tumors can modify their own genes to evade detection and attack by the immune system. A new study in mice reveals how these changes happen and identifies for the first time a comprehensive list of the genes affected.
- By BETH ISRAEL DEACONESS and BOSTON CHILDREN'S COMMUNICATIONS
The work, led by Harvard Medical School researchers at Beth Israel Deaconess Medical Center and Boston Children's Hospital, provides a roadmap for developing therapies that override these genetic changes and restore the immune system's ability to fight cancer.
"No one had done an unbiased study of this before, because by the time a tumor becomes detected it has already finished gene editing," said Judy Lieberman, HMS professor of pediatrics at Boston Children's and co-senior author of the study with Winston Hide, HMS associate professor of pathology at Beth Israel Deaconess.
The findings, published in Nature Immunology, indicate that tumors edit the activity of multiple genes to avoid immune recognition. But the team also shows a way to override these edits and curb tumor growth in a mouse model of breast cancer, which is notoriously resistant to immunotherapy.
If the findings translate to humans, they could inform the design of improved cancer immunotherapies that provide benefit to broader groups of people. While such therapies - such as CAR T cells and immune checkpoint inhibitors - have saved the lives of many patients, they currently don't work for most solid tumors.
The authors suggest that altering the activity of certain genes is a common defense mechanism across cancers.
"Our research sheds light on the sophisticated strategies tumors use to hide from the immune system," said Hide. "By identifying the specific genes that tumors silence to evade detection, we open the door to new therapeutic approaches. These findings could lead to the development of more targeted immunotherapies, potentially improving outcomes for patients with cancer."
Taking stock of cancer edits
To capture how cancers modify genes, the researchers tracked breast tumors from their earliest development.
After turning on the Her2 oncogene in their mouse model, they used genome-wide single-cell RNA sequencing to identify which genes the newly formed tumor was targeting. They did this twice: one week and one month after the gene was switched on.
The team found that many of the genes the tumors affected are involved in the innate immune response, the body's first line of defense against pathogens and disease. Most notable were genes that are stimulated by interferon and enable immune cells to recognize tumor danger signals.
The tumors silenced these genes epigenetically - meaning they did not alter the genetic code itself but instead chemically modified, or methylated, the genes' promoter sequences. The changes reduced activation of the tumors' immune-alerting signals and effectively suppressed immune activity.
Surprisingly, the team found that the tumors modified relatively few genes associated with enhanced proliferation.
"While the tumor also mutates to become more malignant, the dominant changes were immune," said Lieberman.
Fighting back
Lieberman and colleagues found that the FDA-approved drug decitabine, a chemotherapy drug that inhibits methylation and slows cancer cell growth, could reverse these gene expression changes in the mice.
At low doses, decitabine reactivated the immune response and led to reduced tumor growth.
Studying implanted breast and melanoma tumors, they found that decitabine restored function of genes involved in the innate immune system's danger-signaling pathways. These included pathways involving interferon and an inflammatory cell-death pathway known as pyroptosis.
"There was a strong overlap between the genes the tumor edited early on and the genes awakened by the drug," Lieberman noted.
The work grew out of the Lieberman lab's interest in gasdermin E, a potent tumor suppressor gene that triggers pyroptosis and that cancers repress through methylation.
The authors plan to explore how their insights apply to other solid tumors, such as lung and ovarian cancers, and study similar gene expression editing in people with genetic predispositions to cancer, especially at early tumor stages and during metastasis.
Adapted from a Boston Children's blog post and Beth Israel Deaconess news release.
