Novel glycoengineering approach to steer the immune system

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Christian Büll and Torben Heise, PhD candidates in the Adema (Radiotherapy & OncoImmunology Lab, Radiation Oncology) and Boltje (Molecular Chemistry) research groups respectively, published a research paper in the prestigious chemistry journal Angewandte Chemie, International Edition

In this collaborative research between the RIMLS themes Nanomedicine and Cancer development and Immune defense, a glycoengineering approach was developed that allows reprogramming sialic acid sugar interactions with Siglec immune receptors on living cells. Sialic acid sugars are located at the outer end of cell surface glycans. They form the ligands for the sialic acid binding immunoglobulin- like lectin (Siglec) family, which are immunomodulatory receptors expressed by immune cells. Interactions between sialic acid and Siglecs regulate the immune system, and aberrations contribute to pathologies like autoimmunity and cancer. Cancer cells particularly express high levels of sialic acids on their surface that enable them to interact with Siglecs on immune cells to escape from recognition by the immune system and to become resistant against cancer immunotherapy. Sialic acid/Siglec interactions between living cells are difficult to study owing to a lack of specific tools. In this study, the team reports on a glycoengineering approach to remodel the sialic acids of living cells and their binding to Siglecs. Using bioorthogonal chemistry, a library of cells with more than sixty different sialic acid modifications was generated that showed dramatically increased binding toward the different Siglec family members. Rational design reduced cross-reactivity and led to the discovery of selective Siglec ligands. Using glycoengineered cells with high affinity binding to Siglec-3 (CD33) key pathways in monocytes known to be involved in immune regulation like the NF-κb and IRF pathways were regulated. In the future, chemically modified sialic acid sugars with altered Siglec binding characteristics could be applied to control the sialic acid-Siglec axis for the treatment of autoimmunity, cancer and other diseases. 

Steering Siglec-Sialic Acid Interactions on Living Cells using Bioorthogonal Chemistry, Angewandte Chemie, International Edition. 2017. 13;56(12):3309-3313.




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