Most non-canonical proteins uniquely populate the proteome or immunopeptidome

Cuevas, Maria Virginia Ruiz; Hardy, Marie-Pierre; Hollý, Jaroslav; Bonneil, Éric; Durette, Chantal; Courcelles, Mathieu; Lanoix, Joël; Côté, Caroline; Staudt, Louis M.; Lemieux, Sébastien; Thibault, Pierre; Perreault, Claude; Yewdell, Jonathan W.

doi:10.1016/j.celrep.2021.108815

Cited by 147 publications

(148 citation statements)

References 88 publications

(126 reference statements)

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“…Some of these transcription events give rise to aeTSAs. Alternative TSAs include antigens derived from the apparently noncoding regions, mutational frameshifts, alternative splicing and/or editing of RNA transcripts, non-canonical translation and peptide slicing [140][141][142]196]. Alternative TSAs are less well defined than classical neoantigens, but accumulating evidence suggests that they play a major role in shaping anti-tumor immune responses, while they are largely ignored by currently accepted practices of estimating tumor immunogenicity.…”

Section: Alternative Tsasmentioning

confidence: 99%

“…Importantly, immunization with 3 individual aeTSAs conferred protection in a mouse model of transplantable lymphoma, with the endogenous retroelement-derived TSA producing the best anti-tumor immunity [142]. Yewdell and colleagues used a different proteogenomic approach combining mass spectrometry, ribosomal sequencing [of ribosome-protected RNA fragments] and RNA sequencing, to determine the contribution of non-canonical translation to the generation of pMHC-I complexes in human B cell lymphoma [141]. Around 17% of proteins identified were non-canonical proteins, of which the majority (>70%) were cryptic proteins, derived from transcripts presumed to be non-coding (pseudogenes, non-coding RNAs, processed transcripts, intergenic regions and introns) [141].…”

Section: Alternative Tsasmentioning

confidence: 99%

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MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

Shklovskaya

Rizos

2021

IJMS

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It is now well accepted that the immune system can control cancer growth. However, tumors escape immune-mediated control through multiple mechanisms and the downregulation or loss of major histocompatibility class (MHC)-I molecules is a common immune escape mechanism in many cancers. MHC-I molecules present antigenic peptides to cytotoxic T cells, and MHC-I loss can render tumor cells invisible to the immune system. In this review, we examine the dysregulation of MHC-I expression in cancer, explore the nature of MHC-I-bound antigenic peptides recognized by immune cells, and discuss therapeutic strategies that can be used to overcome MHC-I deficiency in solid tumors, with a focus on the role of natural killer (NK) cells and CD4 T cells.

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Section: Alternative Tsasmentioning

confidence: 99%

Section: Alternative Tsasmentioning

confidence: 99%

MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

Shklovskaya

Rizos

2021

IJMS

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“…A major challenge in this field is to identify novel antigens, or neoantigens, which are not directly encoded from genetic sequences and are absent from standard databases. A significant fraction (approximately 30%) of the antigens are cis - and trans -spliced peptides (3), or are non-canonical peptides derived from noncoding regions or frameshifted genes (4, 5). Identifying peptides derived from non-canonical reading frames typically requires a custom database to be generated from RNA-sequencing, followed by searching LC-MS/MS data against the custom database.…”

Section: Introductionmentioning

confidence: 99%

A facile immunopeptidomics workflow for capturing the HLA-I ligandome with PEAKS XPro

Shan

Krieger

2021

Preprint

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Identifying antigens displayed specifically on tumour cell surfaces by human leukocyte antigen (HLA) proteins is important for the development of immunotherapies and cancer vaccines. The difficulty in capturing an HLA ligandome stems from the fact that many HLA ligands are derived from splicing events or contain mutations, hindering their identification in a standard database search. To address this challenge, we developed an immunopeptidomics workflow with PEAKS XPro that uses de novo sequencing to uncover such peptides and identifies mutations for neoantigen discovery. We demonstrate the utility of this workflow by re-analyzing HLA-I ligandome datasets and reveal a vast diversity in peptide sequences among clones derived from a colorectal cancer tumour. Over 8000 peptides predicted to bind HLA-I molecules were identified by de novo sequencing only (not found in the UniProt database) and make up over 50% of identified peptides from each sample. Lastly, tumour-specific mutations and consensus sequence motif characteristics are defined. This workflow is widely applicable to any immunopeptidomic mass spectrometry dataset and does not require custom database generation for neoantigen discovery.

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“…Insights are especially emerging in cancer biology, where transcription and translation are known to be dysregulated. This leads to the production of "aberrant", possibly rapidly-degraded proteins that are commonly antigenic and presented on the cell surface by the HLA system, offering the prospect of neoantigens (Chong et al, 2020;Laumont et al, 2016Laumont et al, , 2018Ouspenskaia et al, 2020;Ruiz Cuevas et al, 2021). In addition, antigens resulting from disease-specific dysregulated ribosome activity -sometimes called defective ribosomal products (DRiPs) (Rock et al, 2014;Yewdell et al, 1996) -have also been explored.…”

mentioning

confidence: 99%

A community-driven roadmap to advance research on translated open reading frames detected by Ribo-seq

Mudge

Ruiz-Orera

Prensner

et al. 2021

Preprint

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Ribosome profiling (Ribo-seq) has catalyzed a paradigm shift in our understanding of the translational vocabulary of the human genome, discovering thousands of translated open reading frames (ORFs) within long non-coding RNAs and presumed untranslated regions of protein-coding genes. However, reference gene annotation projects have been circumspect in their incorporation of these ORFs due to uncertainties about their experimental reproducibility and physiological roles. Yet, it is indisputable that certain Ribo-seq ORFs make stable proteins, others mediate gene regulation, and many have medical implications. Ultimately, the absence of standardized ORF annotation has created a circular problem: while Ribo-seq ORFs remain unannotated by reference biological databases, this lack of characterisation will thwart research efforts examining their roles. Here, we outline the initial stages of a community-led effort supported by GENCODE / Ensembl, HGNC and UniProt to produce a consolidated catalog of human Ribo-seq ORFs.

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Most non-canonical proteins uniquely populate the proteome or immunopeptidome

Cited by 147 publications

References 88 publications

MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

A facile immunopeptidomics workflow for capturing the HLA-I ligandome with PEAKS XPro

A community-driven roadmap to advance research on translated open reading frames detected by Ribo-seq

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