PHILADELPHIA, PA — A groundbreaking discovery from Dr. Filippo Veglia’s lab at The Wistar Institute has revealed how aggressive brain tumors reprogram immune cells, turning them from cancer-fighters into enablers of tumor progression. The findings, published in Cancer Discovery, could pave the way for new treatment strategies targeting some of the deadliest types of brain cancer, including glioblastoma.
Key Findings
The research focuses on tumor-infiltrating neutrophils, white blood cells that typically attack cancer in its early stages. However, within brain tumors, these neutrophils take on an immunosuppressive role, hindering further immune responses. Veglia’s team found that oxygen-deprived regions of tumors reprogram neutrophils by triggering a molecular process known as histone lactylation. This process activates the ARG1 gene in neutrophils, transforming them into agents that suppress the immune system’s anti-cancer efforts.
Higher levels of the protein CD71, identified on 25-30% of tumor-infiltrating neutrophils, were shown to correlate with these changes. The team also connected glucose metabolism and lactate production — both heightened in the tumor microenvironment — to the immunosuppressive transformation.
Potential Therapeutic Breakthrough
By targeting this process, the researchers developed a promising approach to reverse the neutrophils’ reprogramming. Using the compound isosafrole, which blocks lactate processing, they successfully reduced histone lactylation and ARG1 expression in neutrophils, restoring their ability to support anti-cancer immune responses. When combined with immunotherapy, this approach overcame previous resistance in preclinical models and slowed tumor progression significantly.
Dr. Veglia’s work highlights a critical cancer mechanism and offers a potential strategy to improve outcomes for patients with aggressive brain tumors. “Now that we understand this reprogramming process, we know how to interrupt it,” Veglia stated, underscoring the significance of these findings in advancing brain cancer treatment.
This discovery marks a pivotal step in the effort to combat brain cancers, offering hope for therapies that can unlock the immune system’s potential against these otherwise formidable diseases.
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