[en] Tumour-induced mechanisms of immune evasion hinder immune response to cancer, particularly in melanoma. mRNA translation, by ensuring accurate protein synthesis, regulates cancer phenotypes and immune response, but the underlying mechanisms remain unclear. Here, we reveal how O-sialoglycoprotein endopeptidase (OSGEP), catalysing the tRNA modification N6-threonylcarbamoyladenosine (t6A), drives protein homeostasis in cancer cells to maintain T-cell exclusion and prevent anti-tumour immune response. t6A-deficient melanoma cells disrupt efficient cytoplasmic translation of ANN codons (trinucleotides with A in the first position and N = any nucleotide), causing specific protein aggregation and the formation of integrated stress response-dependent stress granules. We discovered that OSGEP loss triggers melanoma regression by relocating RIG-I to stress granules, leading to its pathway activation. As a result, T-cells are recruited to the tumour site and orchestrate an anti-tumour immune response. Finally, an OSGEP-driven gene signature in melanoma patients is associated with T-cell infiltration and improved overall survival. Together, our findings position t6A tRNA modification as a promising therapeutic target for melanoma treatment.
Research Center/Unit :
Giga-Cancer - ULiège
Disciplines :
Oncology
Author, co-author :
Dziagwa, Cléa ; Université de Liège - ULiège > Faculté de Médecine > GIGA - MASSGPFS
Seca, Christian ; Université de Liège - ULiège > Département de pharmacie
Heusdens, Denis ; Université de Liège - ULiège > Département de pharmacie
Budden, Timothy; Skin Cancer and Ageing Lab, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK ; Department of Dermatology, Salford Royal NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK ; Department of Molecular and Clinical Cancer Medicine, The University of Liverpool, Liverpool, UK
Blomme, Arnaud ; Université de Liège - ULiège > Département de pharmacie
Chariot, Alain ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale ; WELBIO department, WEL Research Institute, Wavre, Belgium
Utikal, Jochen; Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany ; Department of Dermatology, Venereology and Allergology, University Medical Centre Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany ; DKFZ Hector Cancer Institute at the University Medical Centre Mannheim, Germany Cancer Research Centre - Deutsches Krebsforschungszentrum (DKFZ), Mannheim, Heidelberg, Germany
Viros, Amaya ; Skin Cancer and Ageing Lab, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK ; Department of Dermatology, Salford Royal NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, The University of Manchester, Manchester, UK
Rapino, Francesca ; Université de Liège - ULiège > Département de pharmacie ; WELBIO department, WEL Research Institute, Wavre, Belgium
Delaunay, Sylvain ; Université de Liège - ULiège > Département de pharmacie ; Laboratory of RNA dynamics in Cancer, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
Close, Pierre ; Université de Liège - ULiège > Département de pharmacie
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