The study, published in the journal Nature Communications, opens the door to the development of effective drug candidates that fully harness the therapeutic potential of Siglec-15. This knowledge will significantly contribute to the development of new immunotherapies and specific approaches for cancer treatment.
A multidisciplinary research team from CIC bioGUNE, led by Dr. June Ereño Orbea, Dr. Jesús Jiménez Barbero and Dr. Asís Palazón, all Ikerbasque researchers, revealed the structure and mechanism of action of Siglec-15, an immune modulator with great potential in cancer immunotherapy.
The scientific article titled "Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b" has been published in the journal Nature Communications, opening the door to the development of effective drug candidates that can harness the therapeutic potential of Siglec-15.
Recently, Siglec-15 has gained significant interest as a potential therapeutic target due to its distinct expression profile and its potential in cancer treatment. However, the limited understanding of its structure and how it interacts with other molecules had hindered drug development until now.
In this study, the research team from CIC bioGUNE, in collaboration with scientists from the Nova School of Science and Technology in Lisbon and the Department of Chemistry at the University of La Rioja, elucidated the structure of Siglec-15 and its binding epitope to a blocking anti-Siglec-15 antibody using X-ray crystallography. Through advanced techniques such as saturation transfer difference nuclear magnetic resonance (STD-NMR) and computational calculations, the team elucidated the binding mode of Siglec-15 to different sialylated glycans, carbohydrates strongly associated with various types of cancer, including the sialyl Tn antigen (STn).
The study revealed that the binding of Siglec-15 to STn-lacking T cells depends on the presence of other sialylated glycans. Furthermore, the study identified the leukocyte integrin CD11b as a ligand of Siglec-15 in human T cells. These findings provide a comprehensive understanding of the structural characteristics of Siglec-15 and emphasize the crucial role of glycosylation in controlling the responses of T cells in our immune system.
Dr. María Pia Lenza, Dr. Leire Egia-Mendikute and Dr. Asier Antoñana Vildosola, who participated in the research, expressed their satisfaction with the implications of these findings. They believe that this knowledge will significantly contribute to the development of new immunotherapies for cancer treatment.
Dr. June Ereño Orbea, Dr. Jesús Jiménez Barbero and Dr. Asís Palazón, the lead authors of the study, highlighted the importance of glycosylation for manipulating immune responses.
The findings of this ongoing research at CIC bioGUNE have implications for the design of next-generation cancer immunotherapies. New possibilities are thus emerging that target Siglec-15 or its glycosylated receptors as therapeutic targets.
Reference: Nature Communications. DOI: 10.1038/s41467-023-39119-8
The Centre for Cooperative Research in Biosciences (CIC bioGUNE), member of the Basque Research & Technology Alliance (BRTA), located in the Bizkaia Technology Park, is a biomedical research organisation conducting cutting-edge research at the interface between structural, molecular and cell biology, with a particular focus on generating knowledge on the molecular bases of disease, for use in the development of new diagnostic methods and advanced therapies.
Ikerbasque - Basque Foundation for Science - is the result of an initiative of the Department of Education of the Basque Government that aims to reinforce the commitment to scientific research by attracting, recovering and consolidating excellent researchers from all over the world. Currently, it is a consolidated organization that has 290 researchers/s, who develop their work in all fields of knowledge.
BRTA is an alliance of 4 collaborative research centres (CIC bioGUNE, CIC nanoGUNE, CIC biomaGUNE y CIC energiGUNE) and 12 technology centres (Azterlan, Azti, Ceit, Cidetec, Gaiker, Ideko, Ikerlan, Lortek, Neiker, Tecnalia, Tekniker and Vicomtech) with the main objective of developing advanced technological solutions for the Basque corporate fabric.
With the support of the Basque Government, the SPRI Group and the Provincial Councils of the three territories, the alliance seeks to promote collaboration between the research centres, strengthen the conditions to generate and transfer knowledge to companies, contributing to their competitiveness and outspreading the Basque scientific-technological capacity abroad.
BRTA has a workforce of 3,500 professionals, executes 22% of the Basque Country's R&D investment, registers an annual turnover of more than 300 million euros and generates 100 European and international patents per year.
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