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Targeting hMGL-GalNAc interactions to reverse immune suppression in cancer

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.

Field of science

  • /natural sciences/biological sciences/biochemistry/biomolecules/carbohydrates
  • /medical and health sciences/basic medicine/immunology/immunotherapy
  • /medical and health sciences/basic medicine/immunology
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /medical and health sciences/basic medicine/pharmacology and pharmacy/pharmaceutical drug/vaccines

Call for proposal

H2020-MSCA-IF-2018
See other projects for this call

Funding Scheme

MSCA-IF-EF-ST - Standard EF

Coordinator

ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOMATERIALES- CIC biomaGUNE
Address
Paseo Miramon 182, Parque Tecnologico De San Sebastian Edificio Empresarial C
20009 San Sebastian
Spain
Activity type
Research Organisations
EU contribution
€ 172 932,48