Dataset Information

Chemotherapy-induced codon-specific immunopeptidome diversification

ABSTRACT: Deregulated mRNA translation in cancer is a source of aberrant protein production when tryptophan shortage is induced by anti-tumor immunity (refs). Tryptophan is decoded by only one codon, and currently the consequences of aberrant protein production in conditions of a shortage of amino acids decoded by multiple codons are unknown. Leucine is decoded by six codons, and its levels influence a variety of key processes in cancer, including the control of mTOR signaling (ref) and epithelial to mesenchymal transition (PMID: 28274951). Here, we show that both leucine deprivation and DNA damage elicit ribosomal stalling and subsequent aberrant protein production predominantly at one codon for leucine, UUA. Mechanistically, we found that the leucine tRNA lowest in abundance is causative for ribosomal stalling and aberrant protein production. In addition, UUA-induced aberrant protein production impacts the landscape of neoepitopes presented at the surface of cancer cells, which can elicit T-cell recognition and killing. Altogether, codon-specific induction of neoepitopes by chemotherapy and leucine diet opens up new avenues for the development of adoptive T cell therapies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Prostate Cancer Cell Line, Breast Cancer Cell Line

DISEASE(S): Prostate Cancer,Breast Cancer

SUBMITTER: Onno Bleijerveld

LAB HEAD: Onno B Bleijerveld

PROVIDER: PXD044085 | Pride | 2025-05-06

REPOSITORIES: Pride

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			Action	DRS
	20221006_Fusion_Project_617_s01_fr01.raw	Raw
	20221006_Fusion_Project_617_s01_fr02.raw	Raw
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Chemotherapeutic agents and leucine deprivation induce codon-biased aberrant protein production in cancer.

Kochavi Adva A Nagel Remco R Körner Pierre-Rene PR Bleijerveld Onno B OB Lin Chun-Pu CP Huinen Zowi Z Malka Yuval Y Proost Natalie N van de Ven Marieke M Feng Xiaodong X Navarro Jasmine Montenegro JM Pataskar Abhijeet A Peeper Daniel S DS Champagne Julien J Agami Reuven R

Nucleic acids research 20241201 22

Messenger RNA (mRNA) translation is a tightly controlled process frequently deregulated in cancer. Key to this deregulation are transfer RNAs (tRNAs), whose expression, processing and post-transcriptional modifications are often altered in cancer to support cellular transformation. In conditions of limiting levels of amino acids, this deregulated control of protein synthesis leads to aberrant protein production in the form of ribosomal frameshifting or misincorporation of non-cognate amino acids ...[more]

PMID: 39588782

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Project description:Many tumors escape by activating multiple cellular pathways that induce immunosuppression. One pivotal immune-suppressive mechanism is the production of tryptophan metabolites along the kynurenine pathway by IFNγ-induced IDO1 enzyme production 4-8. Phase III clinical trials using chemical inhibition of IDO1 in combination with PD1 pathway blockade, however, failed to improve melanoma treatment 9-12. This points at an incomplete understanding of the role of IDO1 and the consequent tryptophan degradation on mRNA translation and cancer progression. Here, we investigated the effects of prolonged IFNγ treatment on mRNA translation in melanoma cells by ribosome profiling. Surprisingly, we observed a massive accumulation of ribosomes ~20 amino acids downstream of tryptophan codons (termed here as W-Bumps) along with their expected stalling at the tryptophan codon itself. This indicated ribosomal bypass of the tryptophan codons in the absence of tryptophan. Detailed examination of W-Bumps position and its corresponding peptide sequences pinpointed towards ribosomal frameshifting events and their effects in the ribosome exit tunnel. In particular, W-Bumps strength was associated with the disorderedness level of potential out-of-frame peptides predicted downstream of tryptophan codons. Indeed, reporter assays demonstrated the induction of ribosomal frameshifting, and the generation of trans-frame proteins and their presentation at the cell surface after IFNγ treatment. Proteomics and immunopeptidomics analyses verified the production of IFNγ-induced trans-frame and out-of-frame aberrant peptides and their presentation on HLA class I molecules. Priming of naïve T cells from healthy donors with aberrant peptides resulted in identification of reactive, peptide-specific T cells. Altogether, our results suggest that IFNγ-induced IDO1-mediated tryptophan depletion plays a role in the immune recognition of melanoma cells by contributing to the diversity of the peptidome landscape, and by inducing the presentation of aberrant peptides.