MGLycan · Targeting hMGL-GalNAc interactions to reverse immune suppression in cancer
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-06-01 → 2021-10-08
- EU contribution
- €172,932
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Targeting hMGL-GalNAc interactions to reverse immune suppression in cancer
Cancer cells communicate with immune cells to persuade them to preclude an immune response. More in depth, the malignant cells mimic healthy cells by displaying a kind of molecules known as glycans. Besides, immune cells such as Dendritic Cells (DC) present a surface populated by lectins, lectins are proteins that interact with glycans. One of these lectins is MGL that is over expressed in immature Dendritic Cells (iDC). iDC are related with the regulation of the immune response. Thus, MGL is an appropriate target to block the immune response. Cancer cells employ their glycans to interact with MGL present in DC aborting the immune reaction and, facilitating the cancer evasion and progression. This key communication happens more frequently with iDCs due to the MGL up regulation. Therefore, it is needed a strategy to foster the maturation of DCs that would help to our natural defenses to trigger an effective immune response. In this line, we propose: A) Glycomimetics library able to bind tightly to the MGL to block cancer-DCs glycan mediated communication. B) Build up a nanoparticles to take advantage of the multivalency to strength the binding. Conclusions. New synthetic approach to accelerate the glycomimetic obtaining has been developed. New glycomimetic library has been synthesized.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- ASOCIACION CENTRO DE INVESTIGACION COOPERATIVA EN BIOMATERIALES- CIC biomaGUNE · San SebastianCoordinatorSpain
Links
Data: CORDIS, © European Union