The study, published in the journal ‘Immunity’ (Cell Press), reveals that when suppressive myeloid cells approach the tumor environment, they modify the sugars (glycans) that decorate certain receptors on their surface. These glycans act as a barcode or ID that is recognized by a protein abundant in the tumor microenvironment: galectin-1.
The binding of galectin-1 to suppressive myeloid cells triggers profound changes by activating the transcription factor STAT3, enhancing these cells’ ability to suppress T lymphocytes (the cells that destroy tumors) and to promote the formation of new blood vessels. Interestingly, this phenomenon is exclusive to the tumor microenvironment and does not occur when these cells are located in other organs such as the spleen or lymph nodes.
This discovery led researchers to analyze samples from cancer patients. They found that tumors with high levels of galectin-1, particularly those associated with colorectal cancer, harbored more activated suppressive myeloid cells, which were associated with a worse clinical prognosis.
Moreover, in patients with colon cancer and melanoma who did not respond to immunotherapy, these cells showed a signature of sugars highly permissive for galectin-1 binding, reinforcing their pro-tumoral profile, thus explaining a new mechanism of resistance to these therapies.
The scientists also identified the complex of cell receptors to which galectin-1 binds (particularly the alphaMbeta2 integrin), triggering a cascade of signals that drive immunosuppression and blood vessel formation.
Based on this knowledge, they developed a strategy to block this circuit: using a neutralizing antibody against galectin-1 developed in their laboratory, or by inhibiting the synthesis of key sugars, they were able to reprogram these cells towards an inflammatory and anti-tumoral profile, reducing tumor growth in experimental models.
The researchers affirm that this finding not only opens a new window to understand how tumors manipulate the immune system but also offers a promising way to enhance current immunological and anti-angiogenic therapies, allowing the use of a single therapeutic agent (anti-GAL1 antibody) to block both processes in tumors resistant to these therapies. «The possibility of reprogramming suppressive myeloid cells constitutes a key strategy in the fight against different types of cancer,» they assure.
The study was conducted by Ada Blidner, a research assistant at the National Scientific and Technical Research Council (CONICET) in Argentina, at the Glicomedicine Laboratory of the Institute of Biology and Experimental Medicine (IBYME), under the direction of Gabriel Rabinovich, a senior researcher at CONICET and full professor at the Faculty of Exact and Natural Sciences of the University of Buenos Aires (Argentina).
Diego Croci and his team from the Vascular Biology Laboratory of IHEM (CONICET-Mendoza) also participated, along with Camila Bach, Alfredo García, Nadia Bannoud, and Joaquín Merlo, fellows and researchers from both laboratories in collaboration with a network of scientists from the Functional Glycomics Laboratory of IBYME, Faculty of Pharmacy and Biochemistry of UBA, and Faculty of Medicine of the National University of La Plata.
FUENTE