Turning “Cold” Pediatric Brain Tumors Into Targets for the Immune System

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. 

To deliver the therapy, the UCSF team worked with collaborator Peng Zhang, PhD, an assistant professor at Northwestern University, to package small RNA molecules inside lipid nanoparticles — tiny fat-based particles similar in concept to delivery systems used in mRNA vaccines. These nanoparticles carried instructions to reduce the production of PP2A inside tumor cells. Mice treated with PP2A-targeting lipid nanoparticles lived significantly longer than mice that received control nanoparticles. In their preclinical medulloblastoma models, the scientists showed that without PP2A, the tumor cells then had more MHC class I proteins that, when present on the surface of cells, enable T cells to recognize and destroy the tumor. 

Having worked in the pharmaceutical industry for years before returning to academia, Lu hopes to further develop this work into a new therapy to bring back to patients. 

“For me, research does not stop when you publish,” Lu said. “My goal is to develop new therapeutics that can help patients and bring hope to families facing devastating cancers.” 

She and Ho, a pediatric neurosurgeon, are in the early stages of designing a clinical trial for pediatric brain cancers.

The implications may also extend beyond medulloblastoma. Because PP2A helps regulate immune visibility in cancer cells, the same strategy could be relevant to other “cold” tumors that have been difficult to treat with immunotherapy, including ovarian and prostate cancers.

“We started with pediatric brain cancer,” Lu said, “but this work may apply to many tumors that currently do not respond well to immunotherapy.”