Glioblastoma Multiforme (GBM): investigating the mechanisms by which the tumor glyco-code modulates anti-tumor immunity

Proponente Aurelia Rughetti - Professore Associato
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca

Glioblastoma Multiforme (GBM) is a highly aggressive brain tumor, with a mortality rate of 88% within 3 years and very limited therapeutic options.
So far, novel immunotherapeutic strategies (Immune Checkpoint Inhibitors, DC vaccines) have shown to be limited. It appears that the immunosuppressive networks, established during GBM progression, are responsible for this failure.
Therefore, the understating of the biological mechanisms underlying GBM tumor-immune cells network is fundamental for defining any alternative and efficacious immunotherapeutic strategy.
Dendritic Cells (DCs) play a pivotal role in initiating and shaping the immune response. Their activation is crucial for triggering and maintaining anti-tumor immunity.
During tumor transformation, novel tumor glycan structures, similar to the ones carried by pathogens, are generated. DCs recognize such aberrant glycans by the C-Type lectin receptors and become activated.
In brain tumors, the immunogenic Tn glycan moiety (GalNAc-O-Ser/Thr) is highly expressed. This tumor associated carbohydrate residue is specifically recognized by the MGL C-type lectin. We have previously shown that MGL engagement by Tn-glycoproteins finely tunes DC performance.

Aim of this proposal is to investigate the impact of tumor Tn glycosylation on DCs functions in the context of GBM. Tn-glycoproteins expressed in GBM tumors will be isolated by their ability to bind MGL employing a modified chromatography technique and identified by Mass/Spec adapted for analysis of glycopeptides.
It will be characterized the ability of the identified GBM associated Tn-glycoproteins to modulate functions of specific DC subsets and activate T cell response in GBM patients.
Results obtained from this study will contribute to decipher the biological mechanisms underlying the GBM tumor cells-DCs interactions mediated by Tn glyco-code. Furthermore, targeting glycans could offer new therapeutic opportunities for GBM patients.

LS6_4, LS6_2, LS6_3

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