TCR beta sequencing of CD4+ Tcells infiltrating melanoma B16 control or depleted of Elp3
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. Here we show that ablation of enzymes catalyzing wobble uridine (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 presented on MHC-II. The remodeled MHC-II repertoire in turn induces a CD4+ effector T cell-mediated anti-tumor response displaying specific clonal selection and immunodominance in melanoma. 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.