Abstract 6359: Structural insights into Siglec-15 reveal glycosylation dependency for interaction with T cells through integrin CD11b

Abstract

Abstract Sialic acid-binding Ig-like lectin 15 (Siglec-15) is emerging as an immune modulator and target for cancer immunotherapy. However, limited knowledge regarding the mechanism of action, structure and binding partners on T cells restrains the development of drug candidates that unleash its full therapeutic potential. Here, we solve the crystal structure of Siglec-15 and delineate its binding epitope by co-crystallization with an anti-Siglec-15 blocking antibody. Saturation transfer-difference (STD) nuclear magnetic resonance (NMR) spectroscopy assisted with molecular dynamic simulations revealed the binding mode of Siglec-15 to the cancer-associated sialyl-Tn (sTn) glycoform. Binding of Siglec-15 to T cells, which lack sTn expression, depends on the presence of sialic acid. We identified the leukocyte integrin CD11b as a binding partner of Siglec-15 on human T cells. Collectively, these data provide an integrative understanding of the structural features of Siglec-15 and underscore glycosylation as an additional layer of control of T cell responses. Citation Format: Maria Pia Lenza, Leire Egia-Mendikute, Asier Antoñana-Vildosola, Cátia O. Soares, Francisco Corzana, Iker Oyenarte, Filipa Marcelo, Jesús Jiménez-Barbero, June Ereño-Orbea, Asis Palazon. Structural insights into Siglec-15 reveal glycosylation dependency for interaction with T cells through integrin CD11b [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6359.