A significant proportion of cancer patients do not respond to therapies with so-called immune checkpoint inhibitors (ICI). The reasons for this are largely unclear. This also applies to patients suffering from chronic lymphocytic leukemia, the most common form of blood cancer in adults in Europe.
A research team led by Martina Seiffert at the DKFZ has now analyzed the immune system of CLL patients in unprecedented depth using state-of-the-art single-cell technologies. The researchers found that certain T cells in the patients' lymph nodes are severely depleted. The fatal consequence of this is that depleted T cells lose their ability to effectively fight cancer cells. Galectin-9, a sugar-protein compound secreted in large quantities by leukemia cells, plays a key role in this depletion. Galectin-9 binds to the TIM-3 receptor on the surface of T cells, which acts as a brake on the immune system.
In mice, the researchers were able to show that blocking galectin-9 significantly improves the immune response and slows tumor growth. High galectin-9 concentrations were also associated with a poorer prognosis in other types of cancer, such as kidney and brain tumors – a promising indication of the broad relevance of this mechanism.
"In CLL and other types of cancer, high expression of galectin-9 correlates with poorer survival rates. This is a strong indication of its role in immune defense and its potential as a therapeutic target,“ says Martina Seiffert, adding: ”With our work, we want to pave the way for the development of new immunotherapies that will also benefit patients who have not responded to existing immunotherapies.”
Llaó Cid L, Wong JKL, Fernandez Botana I, Paul Y, Wierz M, Pilger L-M, Flörchinger A, Tan CL, Gonder S, Pagano G, Chazotte M, Bestak K, Schifflers C, Iskar M, Roider T, Czernilofsky F, Bruch P-M, Mallm JP, Cosma A, Campton DE,Gerhard-Hartmann E, Rosenwald A, Colomer D, Campo E, Schapiro D, Green EW, Dietrich S, Lichter P, Moussay E, Paggetti J, Zapatka M, Seiffert M: Integrative Multi-Omics Reveals a Regulatory and Exhausted T-Cell Landscape in CLL and Identifies Galectin-9 as an Immunotherapy Target
Nature Communications 2025, DOI: doi.org/10.1038/s41467-025-61822-x
