How do brain cancers reprogram immune cells to encourage tumor growth?

A mechanism underlying neutrophil reprogramming in brain cancers has been uncovered, illuminating potential therapeutic targets to stop their pro-cancer effect.

Tumor-infiltrating neutrophils are known to enable brain tumor growth and prevent immunotherapies from working, yet the mechanism underlying neutrophil reprogramming from helpful to harmful remains unresolved. Now, researchers from the Filippo Veglia lab at The Wistar Institute (PA, USA) have uncovered this mechanism and a potential therapeutic approach to counteract it.

In the early stages of cancer, neutrophils play a protective role within the immune system by attacking cancer cells. Yet, at some point, neutrophils are reprogrammed to work for the tumor, suppressing the immune system’s anti-cancer interventions.

Glioblastoma is an aggressive form of brain cancer associated with poor clinical outcomes and high frequencies of tumor-infiltrating neutrophils, a previously identified key factor in preventing a response to immunotherapy. Therefore, the current research team set out to identify how glioblastoma reprograms tumor-infiltrating neutrophils to become immunosuppressive.

The researchers investigated a subset of neutrophils found nearly exclusively within brain tumors of preclinical models. They found that 25–30% of these neutrophils expressed the CD71 protein while very few neutrophils outside the tumor expressed this protein.

They also observed that CD71⁺ brain tumor-infiltrating neutrophils reduced immune system activity, which was heightened in hypoxic environments, such as some regions of the brain tumor microenvironment. Further investigation revealed that hypoxic CD71⁺ neutrophils expressed an additional gene, ARG1, which caused the immunosuppressive effect. But how do neutrophils acquire this gene? The team hypothesized that glucose and lactate play a key role in ARG1 expression, observing that hypoxic environments induced metabolic changes in CD71⁺ neutrophils, such as increasing glucose metabolism and lactate accumulation. When researchers inhibited CD71⁺ neutrophils’ ability to process both glucose and lactate, the neutrophils lost their ability to suppress immune responses, supporting their hypothesis.

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This led the researchers to another question: why would glucose metabolism and lactate accumulation cause ARG1 to be expressed?

Previous research has demonstrated that gene expression can be altered via histone lactylation. In this process, by-products of incompletely metabolized lactate attach lactyl groups to histones, modifying histones and altering gene expression. The researchers confirmed higher levels of histone lactylation markers in CD71⁺ neutrophils compared to CD71^– neutrophils. Additionally, the histone lactylation markers were high in the region of the ARG1 gene, indicating that this process was responsible for ARG1 expression and subsequent immunosuppressive effects. The researchers also demonstrated that ARG1 expression could be reduced by selectively turning off the neutrophils’ ability to carry out histone lactylation.

With a better understanding of neutrophil reprogramming, the researchers then turned their attention to developing a therapeutic approach to counteract it. This involved utilizing the anti-epileptic compound isosafrole, which targets a key lactate-processing enzyme. In a preclinical test, isosafrole impaired ARG1 expression and the immunosuppressive effects of CD71⁺ neutrophils. Next, isosafrole treatment was tested in combination with an immunotherapy that was previously deemed ineffectual due to the cancer’s immunosuppressive ability. “…preclinical data show that isosafrole treatment that disrupts neutrophil reprogramming can make poor-prognosis brain tumors responsive to immunotherapy,” commented Veglia.

Having uncovered a previously unknown mechanism of neutrophil reprogramming, this study highlights potential therapeutic targets for treating aggressive brain cancers. “We look forward to seeing how future research can refine this strategy to fight some of the deadliest cancers,” concluded Veglia.