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.
Glioblastomas (GBM) are the most frequent brain tumors, representing 60% of primary brain tumors and have the worst prognosis with less the 3% survival at 5 years. No effective treatment is available and immunotherapy represents an attractive mode of intervention, offering the advantage of being highly specific with minimal toxicity. However, little is known on the immunological networks that are involved in anti-tumor immune responses and are hampered during tumor progression.
This proposal blends together two actively expanding fields of biomedical research: cancer immunotherapy and glycobiology. During tumor transformation, aberrant glycosylation occurs thus novel tumor specific glycoepitopes appear and are able to differently interact with the immune system.
In particular, the modulation of DC function is crucial for the understanding of the dynamic of the immune response, envisaging possible immunotherapeutic interventions.
This project is finalized to identify tumor associated Tn-glycoantigens expressed by GBMs that are able to modulate DC function through binding of the C-type lectin MGL and to verify their immunogenicity.
The project take advantage of a longstanding collaboration between the Proponent and the Glycomic Center of Copenhagen, directed by Prof.H.Clausen, a leader institution in the field of glycobiology and the solid expertise of the proponent in the study of dendritic cells for cancer therapy.
Results obtained will provide insight for immune recognition mechanisms that can be exploited for the design of cancer vaccines (DC targeting and DC based vaccines). Furthermore, the identified Tn-glycoproteins whose expression is strictly associated with GBM disease can become target for other immune intervention strategies (specific antibody targeting, specific CAR-T) as it is for other solid tumors (20).