Immunotherapy has transformed care for some childhood cancers, but it has not yet worked well for medulloblastoma, one of the most common and aggressive types of brain cancers in children. These tumors often remain “cold”: their cancer cells have ways of hiding from the immune system, making them nearly invisible to T cells that would otherwise recognize and attack them.
New research from UC San Francisco may help change that.
Scientists led by Rongze “Olivia” Lu, PhD, and Winson Ho, MD, principal investigators in the UCSF Brain Tumor Center, have identified a way to help expose these hidden tumor cells. By blocking an enzyme called protein phosphatase 2A (PP2A), the team showed that medulloblastoma cells become more visible to the immune system — potentially turning immunologically “cold” brain tumors into tumors the body can recognize and fight.
The findings were published in The Journal of Clinical Investigation.
Although PP2A was initially identified as a tumor suppressor gene, Lu and Ho were among the first to show that inhibiting this enzyme can instead upregulate an anti-tumor response.
The team discovered that blocking PP2A can attack the problem in two ways at once. It pushes medulloblastoma cells into a specific, immune-activating form of senescence — a stress state that not only slows tumor growth but also makes the cancer cells more visible to the immune system.
“In cancer, senescence is complicated,” said Lu, a co-senior author of the study. “Through bioinformatic analysis with Jiyang Yu, PhD, a professor at St. Jude Children’s Research Hospital, we found that senescent cancer cells are not all the same — some suppress immunity, while others activate it. Targeting PP2A could push tumor cells toward a more immune-alert state.”
In effect, the treatment turns previously hidden cancer cells into targets for cancer-fighting T cells.
“That raises the possibility that PP2A targeting could help make medulloblastoma more responsive to immunotherapies such as checkpoint inhibitors or CAR T-cell therapy, immunotherapies that transformed the treatment of other pediatric cancers like leukemia,” Lu said.