New Insights into How Glioblastoma Manipulates Immune Cells

The Wistar Institute has unveiled a groundbreaking discovery regarding the aggressive brain cancer glioblastoma and its interaction with the immune system. Researchers led by Dr. Filippo Veglia have identified a novel mechanism by which glioblastoma reprograms tumor-infiltrating neutrophils, transforming these immune cells from potential defenders against cancer into facilitators of tumor growth. The findings were documented in the journal Cancer Discovery.

Glioblastoma presents one of the most challenging forms of cancer, with a survival rate of approximately one in three individuals diagnosed with this disease living beyond five years. Traditional immunotherapies designed to activate the immune system against specific cancer markers have yielded mixed results, particularly in severe cases like glioblastoma. A significant barrier to these treatments is the presence of tumor-associated neutrophils, which, instead of combating the cancer, suppress immune responses, thereby allowing the tumor to thrive.

The research team focused on a unique subset of neutrophils located within the brain tumor microenvironment. Their analysis revealed that around 25-30% of these tumor-infiltrating neutrophils expressed a specific protein known as CD71, a marker largely absent in neutrophils found outside the tumor.

Upon examining the immunosuppressive capabilities of CD71-positive neutrophils, it was discovered that they significantly diminished immune activity, particularly in hypoxic environments--areas within the tumor that lack oxygen. This effect was not observed in the CD71-negative neutrophils. Further investigation identified that these hypoxic CD71-positive neutrophils expressed the ARG1 gene, which is responsible for their immunosuppressive properties. When the expression of ARG1 was inhibited, even the hypoxic CD71-positive neutrophils lost their ability to suppress immune responses.

The researchers postulated that the interplay between hypoxia and the glucose metabolism of neutrophils was crucial to this reprogramming process. The hypoxic nature of the tumor environment led to increased glucose metabolism and lactate production among CD71-positive neutrophils. This lactate accumulation was linked to the subsequent expression of ARG1.

A pivotal aspect of this study examined how lactate influenced gene expression through a process known as histone lactylation. Histones, which are proteins that regulate gene structure, can be modified in ways that activate or deactivate genes. In this case, lactate by-products attached to histones, resulting in increased ARG1 expression in hypoxic CD71-positive neutrophils.

To validate this mechanism, researchers inhibited histone lactylation, which led to a decrease in ARG1 expression. This breakthrough clarified the sequence: neutrophils infiltrate the tumor, hypoxia recruits CD71-positive neutrophils, increased glucose metabolism promotes lactate production, and the resulting histone lactylation activates ARG1, ultimately suppressing immune function.

Equipped with this understanding, the research team devised a therapeutic strategy using isosafrole, an anti-epileptic drug that inhibits a key enzyme involved in lactate processing. In preclinical trials, treatment with isosafrole successfully reduced histone lactylation, leading to decreased ARG1 expression and restoring immune function in hypoxic CD71-positive neutrophils, without adversely affecting other immune cells.

When combined with targeted brain cancer immunotherapy, which had previously encountered difficulties due to tumor-induced immunosuppression, isosafrole treatment substantially slowed tumor progression in preclinical models.

Dr. Veglia stated that this research elucidates the mechanisms behind how glioblastoma can reprogram neutrophils into impediments for cancer therapy. With this knowledge, there is potential to disrupt the reprogramming process, paving the way for enhanced responses to immunotherapy in challenging brain tumors. Future research aims to refine these strategies to combat some of the most aggressive cancers.