New Study Reveals Unexpected Role of Lymphatic Vessels in Supporting Immune Cells

When tumors develop, they create a supportive structure known as the tumor stroma, which includes blood and lymphatic vessels that provide essential nutrients and ensure proper biological exchanges. While lymphangiogenesis—the development of lymphatic vessels—has often been linked to poor prognoses due to its role in metastasis, a recent study from the University of Geneva (UNIGE) has uncovered an unexpected positive aspect of these vessels.

Researchers focused on the cells that make up the walls of lymphatic vessels, specifically enzymes they express. This discovery indicates that an enzyme called CH25H could play a pivotal role in boosting immune cell function, especially in response to anti-tumor treatments. These findings, published in Nature Communications, suggest a new pathway for enhancing the effectiveness of immunotherapies.

Challenging the Conventional Wisdom on Lymphangiogenesis

The idea that blocking lymphangiogenesis could limit metastasis seemed promising; however, recent studies have shown that such an approach may not be as effective as initially thought.

While lymphatic vessels do promote metastasis, they are also essential for transporting immune cells and activating the anti-tumor immune response.

Stéphanie Hugues, a professor in the Department of Pathology and Immunology and at the Geneva Centre for Inflammation Research at UNIGE, led this investigation. Her team aimed to understand how lymphatic endothelial cells adapt to the tumor environment and influence immune responses.

An Enzyme That Blocks Tumor Defenses

The study examined gene expression patterns in lymphatic endothelial cells from melanoma tumors and healthy mouse skin. They found an overexpression of the CH25H enzyme in tumor-associated lymphatic endothelial cells. This overexpression was also observed in human patients, with higher levels of CH25H linked to better prognosis outcomes.

Strikingly, patients with elevated CH25H levels also benefited more from immune checkpoint inhibitors, a type of immunotherapy.

The CH25H enzyme converts cholesterol into 25-hydroxycholesterol, which is vital for antiviral immunity. In the context of melanoma, 25-hydroxycholesterol seems to impair tumor defense mechanisms by counteracting factors that suppress immune cell activation. This, in turn, enhances anti-tumor immunity.

The Fluid Role of Lymphatic Cells

To further investigate, Hugues’ team genetically removed the CH25H enzyme from mouse lymphatic endothelial cells. This deletion led to a decrease in 25-hydroxycholesterol levels within melanoma tumors, suppressing immune activity and reducing treatment effectiveness.

Conversely, mice vaccinated with tumor antigens showed increased enzyme expression and higher 25-hydroxycholesterol production, leading to enhanced immune cell activation. This supports clinical observations that higher CH25H expression correlates with better immunotherapy responses in patients.

These findings suggest that CH25H could serve as a biomarker to predict immunotherapy success, allowing personalized treatment adjustments based on individual patient characteristics.

Lymphatic vessels have traditionally been viewed as mere transport pathways. However, this study highlights their complex roles:

Our work clearly shows that the cells that make up lymphatic vessels are highly adaptable. They respond to the tumor microenvironment and immune system modulations.

The tumor stroma is not just a passive scaffold; it is a dynamic microworld with both beneficial and harmful functions. Researchers recommend targeting specific lymphatic vessel functions rather than eliminating lymphangiogenesis entirely to better combat diseases.

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