When a tumor develops, it creates a structure around itself called tumor stroma, within which blood and lymphatic vessels ensure nutritional and respiratory biological exchanges. Lymphangiogenesis, that is, the development of lymphatic vessels is generally associated with a bad prognosis, since it favors the spread of metastasis to other organs. When studying the cells that make up the wall of lymphatic vessels, a team from the University of Geneva (UNIGE) has made an unexpected discovery: an enzyme they express seems to play a key role in supporting immune cells, particularly when they are activated by antitumor treatments. These results, published in Nature communicationsI could pave the way to improve the effectiveness of immunotherapies.
Block lymphartiogenesis to limit the risk of metastasis? The idea seemed promising, but turned out to be disappointing. “While it is true that lymphatic vessels promote metastases, they are also essential to transport immune cells and activate the anti -peasant immune response,” explains Stéphanie Hugues, a full professor in the Department of Pathology and Immunology and in the center of gin for research of inflammation in the Faculty of Medicine of UNIGE, which directed this research. answer.”
An enzyme that blocks tumor defenses
The research team measured the gene expression of lymphatic endothelial cells, the cells that make up the wall of lymphatic vessels, melanoma and in the healthy skin of the mouse. They detected an overexpression of an enzyme called CH25H in the lymphatic endothelial cells associated with tumors, a result confirmed in humans: the more lymphatic vessels contained the melanomas, the more this enzyme was overexpressed. “In addition, patients with high levels of this enzyme had a better prognosis, an effect that was even more pronounced in those treated with a particular type of immunotherapy, immune control point inhibitors,” explains Stéphanie Huges.
The function of this enzyme is to convert cholesterol into 25-hydroxychchinker, an important cholesterol metabolite in antiviral immunity. In melanoma, this enzyme also seems to have an impact on the immune system, probably by undermining tumor defense mechanisms. In fact, the tumor microente naturally produces factors that inhibit the activation of immune cells. However, the 25-hydroxycolsterol avoids this inhibition and, therefore, allows a better activation of antitumor immunity.
The multiple roles of lymphatic cells
Professor Hugues team then eliminated this enzyme in mouse lymphatic endothelial cells. His absence led to a strong fall in the levels of 25-hydroxycollesterol in melanoma tumors, followed by a suppression of immune activity that leads to a much less effective struggle against the disease. In contrast, mice vaccinated with tumor antigens showed a clear increase in the expression of the CH25H enzyme and in the production of 25-hydroxyclesterol, which leads to a better activation of immune cells. This is consistent with clinical observations: in patients under immunotherapy, the level of expression of this enzyme gives an indication of the response to treatment. “Therefore, our discovery could provide a biomarker to predict the success of immunotherapy, allowing treatments to adjust according to the specific characteristics of each patient,” adds Stéphanie Hugues.
Lymphatic vessels have been considered for a long time as simple transport routes. ” Our work clearly shows the much more complex role of the cells that invent them. Highly malleable, they respond to the tumor microenvironment and modulations by the immune system. Therefore, stroma is not only a scaffold for the tumor, but it constitutes a highly complex microwave with beneficial and pathological roles. Therefore, we recommend not directing lymphartiogenesis as a whole, but modular the specific functions to combat the disease more effectively, “the authors conclude.