Children's Hospital of Philadelphia Researchers Find that Missing Messenger RNA Fragments Could be Key to New Immunotherapy for Hard-to-Treat Tumors
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PHILADELPHIA, Aug. 15, 2025 ~ A recent study conducted by researchers at Children's Hospital of Philadelphia (CHOP) has identified a potential new target for immunotherapy in pediatric high-grade glioma tumors. Led by senior study author Andrei Thomas-Tikhonenko, PhD, the team discovered that tiny pieces of messenger RNA (mRNA) are missing in these tumors but not in normal brain tissues. This missing RNA may play a crucial role in making these difficult-to-treat tumors more responsive to immunotherapy.

The study, published in the journal Cell Reports, highlights the need for safe and effective therapies for aggressive brain tumors. While adoptive immunotherapies with CAR-T cells have shown promise, they often target healthy cells as well, causing collateral damage. This is especially concerning in the brain, where destroying healthy neurons is not an acceptable outcome. Therefore, a deep understanding of gene expression patterns exclusive to tumor cells is crucial.

The researchers focused on alternative splicing, a process where a single gene can produce multiple proteins by rearranging exons - the building blocks of mRNA - in different combinations. They suspected that splicing in glioma cells may differ from normal brain cells and could potentially lead to new therapeutic targets.

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Upon further analysis, the team found that previous RNA sequencing analyses of high-grade gliomas had failed to account for very short exons called "microexons." These microexons were found to be missing from important surface proteins, including NRCAM (neuronal cell adhesion molecule), which is essential for normal brain cell function.

In pediatric high-grade gliomas, two microexons were consistently skipped during splicing, resulting in a distinct protein structure with unknown function. The researchers discovered that this shortened version of NRCAM was crucial for cancer cell migration and invasion and played a significant role in tumor growth.

This makes the glioma-specific version of NRCAM an attractive target for immunotherapy because it cannot be easily shut down by the tumors. "While microexons may be small, the effects they have on the overall protein structure are quite profound," said Dr. Thomas-Tikhonenko.

The team developed a mouse monoclonal antibody against the glioma-specific version of NRCAM, which worked like a highlighter when mixed with glioma cells. This "painted" the cells and marked them for killing by T cells armed with an immune receptor for mouse antibodies.

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First study author Priyanka Sehgal, PhD, noted that this research could change the way new targets are identified in other solid tumors as well. The team plans to expand their preclinical research and identify a specific form of immunotherapy that could potentially be explored in a clinical trial.

The study was supported by various organizations, including CureSearch for Children's Cancer Foundation Acceleration Initiative and the National Institutes of Health. Additional support was provided by grants from the National Science Foundation and training grants from NIH. The researchers also received support from various foundations, including the Children's Brain Tumor Network and the Chad Tough Foundation.

In conclusion, this study has identified a potential new target for immunotherapy in pediatric high-grade glioma tumors. The team hopes to continue their research and potentially develop new therapies that can specifically target these tumors without causing harm to healthy brain cells.
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