Le lundi 30 juin 2025, Monsieur Christian SECA, titulaire d'un Diplôme de Laurea magistrale in biotecnologie mediche et d’un Certificat de formation à la recherche en sciences biomédicales et pharmaceutiques, présentera l'examen en vue de l'obtention du grade de Doctorat en sciences biomédicaleset pharmaceutiques, sous la direction de Monsieur Pierre CLOSE et de Madame Francesca RAPINO.

Cette épreuve consistera en la défense publique d'une thèse intitulée : «Perturbation of Codon-Specific mRNA Translation Reshapes MHC-II Tumor Antigen». 

Le jury sera composé de :

Alain CHARIOT (Président), Christophe DESMET (Secrétaire), Pierre CLOSE, Michael HOLZEL (Univ. Bonn), Guy JERUSALEM, Thomas MARICHAL, Laurent NGUYEN, Francesca RAPINO, Benoit VAN DEN HEYDE (UCLouvain).

Résumé de la thèse

The tRNA epitranscriptome is composed of a wide variety of base modifications in tRNAs and is emerging as a potential key vulnerability of cancer. Wobble tRNA modifications are required for specific codon decoding during translation and maintenance of protein homeostasis, and support cancer metastasis and resistance to therapy. In this work, we investigate the role of wobble uridine tRNA modification (U34) in the regulation of the melanoma immune response. We show that ablation of enzymes catalyzing U34 tRNA modification (U34 enzymes) remodels the MHC-II-associated antigen repertoire of melanoma by perturbing codon-specific mRNA translation. This perturbation in translation triggers the formation of aggregates that are subsequently degraded through the autophagy-lysosomal pathway and peptides therefore are presented by MHC-II machinery. The remodeled MHC-II-peptide repertoire in turn induces a CD4+ effector T cell-mediated anti-tumor response displaying specific clonal selection and immunodominance. The loss of these enzymes in melanoma cells promoted T cell exhaustion as a sign of sustained activation to persistent tumor antigens. Tumor bearing mice depleted for U34 enzymes and treated with immune checkpoint inhibitors exhibited the best survival rates with no signs of tumor recurrence after two months. Our results identify a novel, potentially tractable, vulnerability of melanoma, in which codon-specific mRNA translation through wobble uridine tRNA modification, optimizes proteome homeostasis, prevents excessive antigen presentation, and limits T cell activity in melanoma.