Researchers at the Icahn School of Medicine at Mount Sinai have identified the immune cell that acts as the architect and coordinator of powerful immune hubs that form inside tumours and plays a key role in antitumor immunity.

This discovery could lead to new strategies for making cancer immunotherapies more effective.

The findings, published in Science, reveal that a specialised immune cell called dendritic cell type 1 is essential for building and maintaining structures known as tertiary lymphoid structures (TLSs).

These organised clusters of immune cells serve as local command centres, or immune "outposts," where the body coordinates attacks against cancer directly within tumours.

Previous research has shown that patients whose tumours contain TLSs often live longer and respond better to immunotherapy.

Until now, however, scientists did not know what controlled the formation and maintenance of these protective immune hubs.

"Our goal was to understand how these immune structures develop and persist inside tumours," says lead study author Raphael Mattiuz, PhD, Instructor in the lab of Miriam Merad, MD, PhD, at the Icahn School of Medicine.

"We found that a distinct subset of dendritic cells acts as the organiser, bringing together different immune cells and keeping the local anti-cancer response active. That gives us an important new target for future therapies.

As part of the experiments, the research team analysed tumour samples from patients with lung, liver, colorectal, kidney and ovarian cancers using advanced imaging techniques that allowed them to see many different immune cell types at once.

They also used spatial gene analysis, which maps where genes are active within a tumour, enabling the scientists to determine exactly where dendritic cells were located and which immune cells they were interacting with.

To test whether dendritic cells were truly responsible for building and maintaining these immune hubs, the investigators developed a new mouse model that closely reproduces the tertiary lymphoid structures seen in human cancers.

Using this model, they selectively removed, activated, or genetically altered dendritic cells at different stages of tumour development.

These experiments showed that dendritic cells are required not only to establish these immune hubs but also to keep them functioning over time.

The researchers found that dendritic cells do far more than simply alert the immune system to cancer.

Once TLSs are established inside a tumour, these cells remain there, continually coordinating immune activity by bringing together cancer-fighting T cells and antibody-producing B cells.

Rather than travelling to nearby lymph nodes, they function as on-site managers, sustaining a strong local immune response, say the investigators.

"We were surprised to see that these rare cells become permanent organisers within the tumour itself," Dr. Mattiuz says.

"They don't just activate cancer-killing T cells. They also help coordinate antibody responses, allowing multiple parts of the immune system to work together where they're needed most."

The findings provide a clearer path toward therapies designed to increase the number or activity of dendritic cells, helping the body build stronger immune hubs inside tumours.

Such approaches could potentially improve existing immunotherapies, particularly for patients whose cancers do not respond well to current treatments.

"This study provides a foundation for developing treatments that strengthen the body's own immune defences against cancer," says senior study author Dr. Merad, the Robin Chemers Neustein Professor of Immunology and Chair of Immunology and Immunotherapy at the Icahn School of Medicine.

"While more research is needed to understand exactly how these immune hubs eliminate tumours, we now have a road map for exploring therapies that could generate more durable anti-cancer responses and, ultimately, help prevent cancer from returning," Dr. Mattiuz says.

Researchers say the findings provide an important foundation for understanding how the immune system mounts a sustained attack on cancer.

They plan to investigate how TLSs generate long-lasting immune protection and whether therapies that activate dendritic cells can enhance immunotherapy, reduce cancer recurrence, and prevent metastasis.

Source: The Mount Sinai Hospital / Mount Sinai School of Medicine