Impact of aberrant O-glycosylation in antigen immune recognition: glycoepitope identification for T cell based anti-cancer immunotherapy

Proponente Aurelia Rughetti - Professore Associato
Sottosettore ERC del proponente del progetto
Componenti gruppo di ricerca
Componente Categoria
Chiara Napoletano Componenti strutturati del gruppo di ricerca
Sabino Carbotta Componenti strutturati del gruppo di ricerca
Marco Biffoni Componenti strutturati del gruppo di ricerca
Componente Qualifica Struttura Categoria
Fabio Scirocchi Borsista Medicina Sperimentale Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca
Veronica Morea Ricercatore CNR Altro personale aggregato Sapienza o esterni, titolari di borse di studio di ricerca

Glycosylation is a complex and highly variable post-translational modification occurring to proteins and lipids. The combinatorial possibility of glycan signatures amplifies and enhances complexity of biological information.
Lectins are the receptors devoted to decipher such biological signals; deregulation of the glycan-lectin circuits results in immune dysfunction.

In epithelial cancer, changes in glycosylation occur since early steps of tumor transformation. Truncated core 2 O-glycans are generated as such as T (Galß1-3GalNAc¿1-O-Ser/Thr), and Tn (GalNAc¿1-O-Ser/Thr) and their sialylated version STn and ST. Their combined expression with protein backbone generates O-glycopeptide motifs that are tumor specific and immunogenic. The possibility to activate a specific immune response towards these tumor glycopeptide structures is extremely challenging for the design of immune intervention strategies.
While glycopeptides epitopes have been identified as target for humoral immune response, there is lack of consensus on T cell recognition of glycopeptides in the context of MHC.

This research project proposes to investigate the impact of Tn-glycosylation on CD8+ T cell activation. The project exploits unpublished results regarding Tn-glycoproteins relevant for tumor-immune cell interactions. MGL C-type lectin, specific for the Tn glycan, has been employed to isolate tumor Tn-glycoproteins. The analysis of glycosites of tumor Tn-glycoproteins will be interpolated with the predicted epitope binder sequences for HLAI-A2.01 molecule obtained by in silico analysis exploiting immune databases. The HLAI-A2.01 binders that are glycosylated in our database will be tested for their immunogenicity in vitro analysis employing immune cells from cancer patients, HLAI-A2.01+.
The final goal of the project is to obtain indication for anti-cancer glycopeptide targeted T cell immunotherapy to be used for designing vaccines or guide CAR-T and ACT therapies.

LS6_4, LS4_6, LS2_13

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