Structural insights into the immune modulator Siglec-15 and its interaction with T cells

The research was first published online [June 13^th, 2023] in the journal Nature Communications

Siglec-15 has emerged as a promising target for therapeutic intervention in the field of cancer treatment, primarily due to its unique expression pattern and potential as an immune modulator. Its distinct expression profile, often found in tumour cells and tumour-associated macrophages, makes it an attractive candidate for targeted therapies aimed at modulating immune responses within the tumour microenvironment. Despite the growing interest in Siglec-15, the development of effective drugs has been hampered by a limited understanding of its structural characteristics and the mechanisms by which it interacts with other molecules. In order to fully exploit the therapeutic potential of Siglec-15, a comprehensive understanding of its structure and molecular interactions is crucial.

A multidisciplinary research team from CIC bioGUNE, led by Jesús Jiménez Barbero, Asís Palazón and June Ereño, through a combination X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and computational modelling elucidated the crystal structure of Siglec-15 and its binding epitope by co-crystallizing it with an anti-Siglec-15 blocking antibody. Using advanced techniques such as saturation transfer-difference nuclear magnetic resonance (STD-NMR) spectroscopy and molecular dynamics simulations, the team unravels Siglec-15's binding mode to α(2,3)- and α(2,6)-linked sialic acids, as well as the cancer-associated sialyl-Tn (STn) glycoform. “These results have revealed that the binding of Siglec-15 to T cells, which lack STn expression, depends on the presence of α(2,3)- and α(2,6)-linked sialoglycans. Additionally, the study identified the leukocyte integrin CD11b as a binding partner for Siglec-15 on human T cells. “These discoveries provide a comprehensive understanding of Siglec-15's structural features and underscore the crucial role of glycosylation in controlling T cell responses”, says June Ereño.

Prof. Jesús Jiménez Barbero emphasized the importance of glycosylation in understanding and manipulating immune responses and, together with all co-authors, they believe that this work has implications for the field of cancer immunotherapy as they offer valuable insights into the structure and interactions of Siglec-15. This understanding opens up new possibilities for the design of next-generation immunotherapies targeting glycosylation or glycan-based pathways, say Asis Palazón.

FUNDING:

This work was supported by the European Research Council (ERC-2017-AdG, 788143-RECGLYCANMR to J.J.-B; ERC-2018-StG 804236-NEXTGEN-IO to A.P.) and the Marie-Skłodowska-Curie actions (ITN Glytunes grant agreement No 956758 to K.S.; ITN BactiVax under grant agreement no. 860325 to U.A. and ITN DIRNANO grant agreement No 956544 to F.C.). X-ray diffraction experiments described in this paper were performed using beamlines XALOC synchrotron at ALBA (Spain) and PXIII in Swiss Light Source (Switzerland). F.M., C.S. and H.C. acknowledge Fundação para a Ciência e a Tecnologia (FCT-Portugal) for funding projects: PTDC/BIA-MIB/31028/2017 and UCIBIO project (UIDP/04378/2020 and UIDB/04378/2020) and Associate Laboratory Institute for Health and Bioeconomy—i4HB project (LA/P/0140/2020), to the CEEC contracts 2020.00233.CEECIND and 2020.03261.CEECIND for F.M. and H.C., respectively, and to PhD grant 2022.11723.BD of C.S. The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project No 22161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). F.M. and J.J.-B. acknowledge to the European funding for the GLYCOTwinning project (No. 101079417) and -COST Action GLYCONANOPROBES. A.P.’s research is funded by “La Caixa” Foundation (HR21-00925), AECC (LABAE211744PALA), Fundación FERO, Ikerbasque, and BIOEF EITB MARATOIA BIO19/CP/002. We thank Agencia Estatal de Investigación of Spain for grants PID2019-107956RA-I00 (A.P.), PID2019-107770RA-I00 (J.E.-O.), RTI2018-099592-B-C21 (F.C.), ID2020-114178GB (R.B. and J.D.S.), RYC2018-024183-I (A.P.), and the Severo Ochoa Center of Excellence Accreditation CEX2021-001136-S, all funded by MCIN/AEI/10.13039/501100011033 and by El FSE invierte en tu futuro, as well as CIBERES, and initiative of Instituto de Salud Carlos III (ISCIII, Spain) A.A.-V. receives funding from “La Caixa” Foundation (ID 100010434, LCF/BQ/DR20/11790022). A. B. (AECC Bizkaia Scientific Foundation, PRDVZ19003BOSC). F.C. acknowledges the Mizutani Foundation for Glycoscience (Grant 220115).

Publication

Lenza et al. Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b. Nature Communications June 13^th, DOI: 10.1038/s41467-023-39119-8.

About CIC bioGUNE

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.

About Ikerbasque

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.