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Arginine deprivation of ASS1-deficient cancers drives mistranslation and shared neoepitope production

ABSTRACT: Arginine biosynthesis is frequently suppressed in human cancer due to loss of argininosuccinate synthetase 1 (ASS1) expression, rendering cancer cells reliant on extracellular arginine. This observation propelled the development of systemic arginine depletion strategies, which are clinically safe but showed limited efficacy. Here, we show that in conditions of arginine scarcity, cancer cells with low ASS1 expression resort to aberrant mRNA translation in the form of ribosomal frameshifts and amino acid misincorporations. While aberrant proteins originated from most arginine codons, the predominant effect was observed at AGA. This codon-preference is caused by a selective decrease of tRNAArg(UCU) levels after arginine deprivation, which is linked to METTL1-mediated tRNA-modification. Using proteomics and immunopeptidomics, we validated that arginine shortage induces aberrant protein and neoepitope production at the endogenous level.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pancreatic Cancer Cell Line, Adenocarcinoma Cell Line, Lung Cancer Cell Line, Cell Line Cell, Melanoma Cell Line

DISEASE(S): Adenocarcinoma,Lung Cancer,Melanoma,Pancreatic Cancer

SUBMITTER: Onno Bleijerveld

LAB HEAD: Onno Bleijerveld

PROVIDER: PXD068912 | Pride | 2026-04-28

REPOSITORIES: Pride

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			Action	DRS
	20231008_Exploris_Evosep_EV1137_Project_748_IP_s01.raw	Raw
	20231008_Exploris_Evosep_EV1137_Project_748_IP_s02.raw	Raw
	20231008_Exploris_Evosep_EV1137_Project_748_IP_s03.raw	Raw
	20231008_Exploris_Evosep_EV1137_Project_748_IP_s04.raw	Raw
	20231008_Exploris_Evosep_EV1137_Project_748_IP_s05.raw	Raw

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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.

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Arginine deprivation of ASS1-deficient cancers drives mistranslation and shared neoepitope production

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