Soutenance de thèse : Structural insights into Siglec-10 receptor : a target for cancer immune modulation

Par Jahnavi Jangala (IBS/Groupe Imagerie microscopique d’assemblages complexes)

Siglecs are transmembrane receptors expressed on surfaces of innate immune cells. They recognize sialic acids used by vertebrates as signatures of “self” but also by some microbial pathogens that thereby modulate host immune responses. Aberrant interactions between Siglecs and their ligands lead to a variety of pathologies such as infection, autoimmune diseases and cancer. Understanding the structural basis of Siglec-ligand binding is therefore a crucial step towards the rational design and development of novel therapeutic and diagnostic strategies against numerous diseases. Siglec-10 is one of the few Siglecs that directly contributes to immune suppression by binding CD24 on tumor cells. The Siglec-10–CD24 pathway is exploited by many cancers to evade macrophage-
mediated phagocytosis and other immune responses, making Siglec-10 a promising target for cancer immunotherapy. In the current study, I determine the structure of the extracellular domain of Siglec-10 by cryogenic electron microscopy, assess the oligomeric state of this receptor by biophysical approaches, address the structural role of its glycosylation, and investigate its interaction with the sialic acid on the target cell surface. Unraveling of the molecular structure of Siglec-10 and characterizing its binding to sialoglycan ligands represent fundamental steps towards deciphering the complex mechanisms regulating host immune suppression.