New study unravels how brain tumors disarm neutrophils and turn them into allies

A groundbreaking study led by Ludwig Lausanne’s Johanna Joyce and her MD-Ph.D. student, Roeltje Maas, has delved into the intricacies of neutrophils, immune cells residing within brain tumors. These tumors include gliomas, which originate in the brain, and cancers that metastasize there from other organs like the lung, breast, and skin.

The research sheds light on the vital role neutrophils play in supporting the survival of brain cancers and unveils the mechanisms by which the tumor microenvironment manipulates these cells, transforming them into promoters of malignant growth. These findings hold promise for novel approaches to treat both gliomas and brain metastases (BrMs).

Joyce explained, “Our study reveals how the brain tumor microenvironment attracts and disarms infiltrating neutrophils, prolonging their typically short lifespans and turning them into cells that stifle anti-cancer immune responses while facilitating the development of blood vessels that nourish the growing cancer.”

Published in Cell, the study meticulously examines the spatial distribution, behavior, gene expression, and functions of neutrophils in BrMs and gliomas. Importantly, it identifies specific cellular interactions and molecular factors in the tumor microenvironment responsible for converting neutrophils from potential defenders against tumors into supporters of malignancy.

Maas emphasized the significance of this discovery, particularly for brain metastases, saying, “This finding is particularly exciting because only a small subset of brain metastases respond to current immunotherapies, and gliomas have proven highly resistant to all treatments. Identifying specific cellular and molecular factors that can transform neutrophils into immunosuppressive and pro-tumor agents opens the door to developing therapies that render brain cancers more vulnerable to immunotherapy.”

Cancers rely on a variety of noncancerous cells to thrive, and brain tumors are no exception. The Joyce lab has been dedicated to exploring the immune landscape of gliomas and BrMs in recent years, seeking new strategies to combat their recurrence and resistance to treatment, with a specific focus on myeloid immune cells, including macrophages and microglia.

Their research revealed that neutrophils, another type of myeloid cell, accumulate in significant numbers in brain tumors, particularly in aggressive gliomas and BrMs, prompting questions about their role in tumor progression. This study provides answers to those questions.

Based on a comprehensive analysis of over 190 brain tumor samples from patients and experiments in various mouse models of brain cancer, the research shows that neutrophils are more abundant in BrMs than in primary gliomas. However, in all tumor types, their physical characteristics and functional behaviors differ significantly from those of neutrophils in the bloodstream and healthy brain tissue.

The researchers found that neutrophils in the tumor microenvironment tend to cluster around abnormal and leaky blood vessels within tumors. They silence gene programs that promote cell death and activate genes that support cell survival, thus extending their lifespans. This phenomenon was validated through studies in mouse models of brain cancer.

Once nestled in the tumor microenvironment, these tumor-associated neutrophils (TANs) actively contribute to the formation of blood vessels and become functionally suppressed, halting the production of reactive oxygen species, which neutrophils typically use to eliminate cellular targets.

However, TANs are not merely passive victims of immunosuppression; they also actively contribute to it. The researchers demonstrate that TANs clustered around tumor blood vessels interact with and suppress cytotoxic T cells, which are the immune system’s frontline warriors against cancer and are engaged by most approved immunotherapies.

The study identifies several factors responsible for recruiting TANs into the tumor microenvironment and inducing their functional transformation. Of particular importance are two inflammatory factors: TNF-α, a signaling molecule, and ceruloplasmin, a copper-carrying protein. These factors are produced by neutrophils themselves, as well as by macrophages and microglia.

Joyce concludes, “This adds to growing evidence that the myeloid niche within the tumor microenvironment plays a central role in creating and maintaining an intensely immunosuppressive environment across various brain tumor types, which supports the survival and progression of these typically lethal cancers.” Her team’s next step is to investigate whether targeting the inflammatory factors and cellular interactions responsible for TAN immunosuppression can enhance the response of brain tumors to immunotherapy.

Source: Ludwig Cancer Research

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