BamQuery: a proteogenomic tool for the genome-wide exploration of the immunopeptidome

Cuevas, Maria Virginia Ruiz; Hardy, Marie-Pierre; Apavaloaei, Anca; Kina, Eralda; Vincent, Krystel; Gendron, Patrick; Laverdure, Jean‐Philippe; Durette, Chantal; Thibault, Pierre; Lemieux, Sébastien; Perreault, Claude; Ehx, Grégory

doi:10.1101/2022.10.07.510944

Cited by 4 publications

(7 citation statements)

References 67 publications

(106 reference statements)

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“…The selected TSAs are predicted binders to HLA allotypes that are highly prevalent in several ethnicities (Figure S1c and Table S2; based on HLA frequency data from [30]). We also evaluated the frequency of expression of their RNA sequences in the TCGA ovarian cancer cohort using the proteogenomic tool BamQuery [31]. We found that all TSAs included in the present study are coded by transcripts expressed in 15 to 100% of the TCGA ovarian cohort, with 33 (69%) shared by at least 40% of the cohort (Figure 1b,c).…”

Section: Selection Of the Best Tsa Candidatesmentioning

confidence: 70%

“…Using BamQuery [31] in manual mode, we quantified the expression of TSA-coding transcripts in ovarian cancer samples (TCGA, n = 377; https://www.cancer.gov/ccg/research/ genome-sequencing/tcga, accessed on 8 March 2017) and normal tissues [(Genotype-Tissue Expression cohort (GTEx) [32] and medullary thymic epithelial cells (mTECs) samples [14,33,34]; Gene Expression Omnibus (GEO) GSE127825 and GSE127826)]. We estimated the proportion of the TCGA ovarian samples with a TSA-coding sequence expression higher than two times the normal 95th percentile value.…”

Section: Evaluation Of Cancer Specificity and Sharing Of Tsa Source T...mentioning

confidence: 99%

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Immunogenicity of Non-Mutated Ovarian Cancer-Specific Antigens

Hesnard,

Thériault,

Cahuzac

et al. 2024

Current Oncology

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Epithelial ovarian cancer (EOC) has not significantly benefited from advances in immunotherapy, mainly because of the lack of well-defined actionable antigen targets. Using proteogenomic analyses of primary EOC tumors, we previously identified 91 aberrantly expressed tumor-specific antigens (TSAs) originating from unmutated genomic sequences. Most of these TSAs derive from non-exonic regions, and their expression results from cancer-specific epigenetic changes. The present study aimed to evaluate the immunogenicity of 48 TSAs selected according to two criteria: presentation by highly prevalent HLA allotypes and expression in a significant fraction of EOC tumors. Using targeted mass spectrometry analyses, we found that pulsing with synthetic TSA peptides leads to a high-level presentation on dendritic cells. TSA abundance correlated with the predicted binding affinity to the HLA allotype. We stimulated naïve CD8 T cells from healthy blood donors with TSA-pulsed dendritic cells and assessed their expansion with two assays: MHC-peptide tetramer staining and TCR Vβ CDR3 sequencing. We report that these TSAs can expand sizeable populations of CD8 T cells and, therefore, represent attractive targets for EOC immunotherapy.

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Section: Selection Of the Best Tsa Candidatesmentioning

confidence: 70%

Section: Evaluation Of Cancer Specificity and Sharing Of Tsa Source T...mentioning

confidence: 99%

Immunogenicity of Non-Mutated Ovarian Cancer-Specific Antigens

Hesnard,

Thériault,

Cahuzac

et al. 2024

Current Oncology

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“…We next sought to explore AZA-induced changes in the immunopeptidome for two reasons: First, because of the disconnect between the number of ERE DEGs and ERE DEMs (Figure 2F) and second, because our initial MAPs of interest (CTAs and EREs) represented only a fraction of AZA-induced MAPs (Figure 2F). To this end, we assessed the global impact of transcriptomic variations on the immunopeptidome using BamQuery, a computational tool that quantifies the RNA expression of any MAP of interest, including those derived from non-annotated genomic regions (36). Most AZA-altered DEMs displayed no change at the RNA level (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Autophagy degrades immunogenic endogenous retroelements induced by 5-azacytidine in acute myeloid leukemia

Noronha

Durette

Silva

et al. 2022

Preprint

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The hypomethylating agent 5-azacytidine (AZA) is the first-line therapy for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. Evidence suggests that the anti-tumor effect of AZA results partly from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) whose expression is induced by hypomethylation. Through a proteogenomic approach, we analyzed the impact of AZA on the transcriptome and MAP repertoire of four AML cell lines and validated salient findings in the transcriptome of 437 primary AML samples. We demonstrate that AZA caused pleiotropic changes in AML cells via perturbation of transcription, translation, and protein degradation. Overall, 1,364 MAPs were upregulated in AZA-treated cells, including several cancer-testis antigens. Increased MAP abundance was due to the upregulation of corresponding transcripts in a minority of cases and post-translational events in most cases. Furthermore, AZA-induced hypomethylation increased the abundance of numerous transcripts, of which 38% were endogenous retroelements (EREs). Upregulated ERE transcripts triggered innate immune responses but were degraded by autophagy and not processed into MAPs. Autophagy resulted from the formation of protein aggregates caused by AZA-dependent inhibition of DNMT2, a tRNA-methyl transferase enzyme. We found that autophagy inhibition had a synergistic effect with AZA on AML cell proliferation and survival, increased ERE levels and triggered pro-inflammatory responses. Finally, autophagy gene signatures were associated with a lower abundance of CD8+ T-cell markers in AML patients expressing high levels of EREs. Altogether, this work demonstrates that the impact of AZA is regulated at several levels and suggests that inhibiting autophagy could improve the immune recognition of AML blasts in patients.

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“…The Python and R scripts generated during this study are available on GitHub: https:// github. com/ lemie ux-lab/ BamQu ery (License: MIT [88]) and Zenodo (doi: https:// doi. org/ 10.…”

Section: Supplementary Informationmentioning

confidence: 99%

“…5281/ zenodo. 78638 16, License: CC-BY-4.0 [89]). BamQuery can be downloaded and installed from https:// bamqu ery.…”

Section: Supplementary Informationmentioning

confidence: 99%

BamQuery: a proteogenomic tool to explore the immunopeptidome and prioritize actionable tumor antigens

et al. 2023

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MHC-I-associated peptides deriving from non-coding genomic regions and mutations can generate tumor-specific antigens, including neoantigens. Quantifying tumor-specific antigens’ RNA expression in malignant and benign tissues is critical for discriminating actionable targets. We present BamQuery, a tool attributing an exhaustive RNA expression to MHC-I-associated peptides of any origin from bulk and single-cell RNA-sequencing data. We show that many cryptic and mutated tumor-specific antigens can derive from multiple discrete genomic regions, abundantly expressed in normal tissues. BamQuery can also be used to predict MHC-I-associated peptides immunogenicity and identify actionable tumor-specific antigens de novo.

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BamQuery: a proteogenomic tool for the genome-wide exploration of the immunopeptidome

Cited by 4 publications

References 67 publications

Immunogenicity of Non-Mutated Ovarian Cancer-Specific Antigens

Immunogenicity of Non-Mutated Ovarian Cancer-Specific Antigens

Autophagy degrades immunogenic endogenous retroelements induced by 5-azacytidine in acute myeloid leukemia

BamQuery: a proteogenomic tool to explore the immunopeptidome and prioritize actionable tumor antigens

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