Neurons and Immune Cells Cooperate to Drive Tumor Growth in Neurofibromatosis Type 1

Summary: Noncancerous neurons and immune cells interact to promote tumor growth in neurofibromatosis type 1 (NF1), revealing new potential therapeutic targets.

Source: Washington University School of Medicine (WUSTL)

Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes people to tumors of the nervous system. New research from Washington University School of Medicine in St. Louis shows that tumor development and progression in NF1 are not driven solely by the tumor cells themselves but by an interactive network that includes nearby noncancerous neurons and immune cells. These findings highlight a neuron–immune–cancer axis that may offer fresh avenues for therapeutic intervention in low-grade gliomas associated with NF1.

Children with NF1 commonly develop tumors on nerves and in the brain; one clinically important example is an optic pathway glioma that can impair vision when it arises in the optic nerve. The new study, published May 1 in Nature Communications, demonstrates that neurons neighboring these gliomas release signals that activate immune T cells. In turn, those activated T cells stimulate other immune cells to secrete growth factors that help sustain and expand the tumor.

“Discovering that nerve cells and immune cells cooperate to support tumor growth changes how we think about tumors that arise within the nervous system,” said senior author David H. Gutmann, MD, PhD, director of the Washington University Neurofibromatosis Center. “These results indicate that neurons are not bystanders but active participants—potentially essential drivers—in the development and maintenance of these tumors.”

NF1 affects roughly one in every 3,000 people and results from mutations in the NF1 gene. While many people with NF1 are diagnosed because of skin findings such as café-au-lait spots, about 20% of children with NF1 will develop a low-grade glioma on the optic nerve (optic glioma). To understand what drives these tumors, the research team led by first author Xiaofan Guo, MD, a graduate student in Gutmann’s laboratory, studied genetically engineered mice with NF1 mutations as well as human cells derived from stem cells.

The investigators had previously observed that optic gliomas are infiltrated by immune cells that contribute to tumor formation. Building on that work, they found that neurons carrying NF1 mutations release the protein midkine. Midkine activates naïve CD8+ T cells, prompting those T cells to produce Ccl4. Ccl4 then triggers microglia, the resident immune cells of the brain, to secrete Ccl5—a factor shown to support glioma stem cell survival and tumor growth. These layered interactions—neuron to T cell to microglia to tumor cell—define a neuron–immune–cancer signaling axis that drives low-grade glioma progression in NF1.

Analysis of clinical datasets supported the experimental results: patients with low-grade gliomas that contained higher levels of CD8+ T cells or elevated CCL5 expression tended to have poorer survival outcomes. To test the functional importance of T cells in tumor growth, the researchers eliminated T cells from mice with optic gliomas or blocked T cell entry into the brain. In both scenarios, optic glioma growth slowed, confirming that T cells are required for full tumor progression in this model.

These results suggest that disrupting communication within the neuron–immune–tumor network could represent an effective therapeutic strategy for NF1-associated low-grade gliomas. Targeting midkine signaling, modulating CD8+ T cell activation, or interfering with the downstream microglial production of tumor-supportive factors are potential approaches that emerge from this work.

“This study adds important insights to the emerging field of cancer neuroscience by revealing how neurons and immune cells cooperate to govern glioma growth,” Gutmann said. “Understanding these intercellular dependencies gives us new opportunities to develop treatments that target the tumor’s supportive environment, rather than only the tumor cells themselves.”

About this research

Institution: Washington University School of Medicine in St. Louis (WUSTL)

Media contact: Judy Martin Finch – WUSTL

Image source: The image used is in the public domain.

Original research

Title: Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth

Authors: Xiaofan Guo, Yuan Pan, Min Xiong, Shilpa Sanapala, Corina Anastasaki, Olivia Cobb, Sonika Dahiya & David H. Gutmann.

Publication: Nature Communications, published May 1. DOI: 10.1038/s41467-020-15770-3

Key findings (concise)

• Neurons with NF1 mutations secrete midkine, which activates CD8+ T cells.
• Activated CD8+ T cells produce Ccl4, inducing microglia to secrete Ccl5, a growth factor for glioma stem cells.
• Higher tumor-associated CD8+ T cell and CCL5 levels correlate with worse survival in low-grade glioma patients.
• Removing or blocking T cells in mouse models reduces optic glioma growth, showing the pathway’s functional importance.

These insights into the neuron–immune–cancer axis in NF1-associated glioma point to novel therapeutic targets that merit further study for the treatment of childhood brain tumors and other low-grade gliomas arising in the nervous system.