Project description
Inhibiting immune suppression in cancer
Tumours are known to evade immune responses, thereby limiting the efficacy of immunotherapy and vaccination efforts. Although cancer cells express aberrant glycosylation patterns, their immunosuppressive role has been largely overlooked. The EU-funded MGLycan project will focus on the macrophage galactose-type lectin (MGL), the key receptor on immune cells that recognises aberrant sugars on cancer cells. MGL is overexpressed in macrophages and dendritic cells during immune suppression. The main objective of the project is to design inhibitors that block the MGL interaction with cancer cells, blocking downstream signalling that culminates in immune suppression.
Objective
The appearance of aberrant glycans on the tumor cell surface is one of the emerging hallmarks of cancer. Tumor growth is accompanied by tumor evasion of the immune system which limits the efficacy of cancer vaccines. However, and despite the fact that aberrant tumor glycosylation alters how the immune system perceives the tumor and, can also induce immunosuppressive signaling through glycan-binding receptors, the role of tumor glycosylation in immune evasion has mostly been overlooked. It is clear that new strategies to avoid the immune escape mechanisms generated by tumor cells are required. The interaction between the immune system and Tumor-Associated Carbohydrates Antigens (TACAs) is facilitated by a diverse set of carbohydrate-binding receptors, as the C-type lectin receptors (CLRs) which mediate specific interactions with TACAs controlling many features of the immune response. The immune escape mechanisms generated by truncated O-glycans, such as Tn antigen (αGalNAc-Ser/Thr) are still poorly understood. Human macrophage galactose-type lectin (hMGL) is a CLR that recognizes terminal GalNAc moieties, and is, therefore, a prime receptor for the aberrant O-glycans in cancer. MGL is upregulated in tolerogenic and immature dendritic cells (DCs) and macrophages playing an important role in immunosuppression. It interacts with effector T-cells, resulting in reduced proliferation, cytokine secretion and induction of T-cell apoptosis. In this project, we propose the design and synthesis of multivalent MGL ligands mimetics with an improved affinity toward this receptor, that will serve as selective inhibitors to reverse GalNAc-mediated immune suppression for cancer immunotherapy.
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Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
20009 San Sebastian
Spain