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Papers by Claude Perreault

Table S5 from Proteogenomics Uncovers a Vast Repertoire of Shared Tumor-Specific Antigens in Ovarian Cancer

Table S5

International Immunology, Nov 1, 2005

Proteins show drastic discrepancies in their contribution to the collection of self-peptides that... more Proteins show drastic discrepancies in their contribution to the collection of self-peptides that shape the repertoire of CD8 T cells (MHC I self-immunopeptidome). To decipher why selected proteins are the foremost sources of MHC I-associated self-peptides, we chose to study SIMP/STT3B because this protein generates very high amounts of MHC I-associated peptides in mice and humans. We show that the endoplasmic reticulum (ER)-associated degradation pathway and MHC I processing intersect at SIMP/STT3B. Relevant key features of SIMP/STT3B are its lysine-rich region, its propensity to misfold and its location in the ER membrane in close proximity to the immunoproteasome. Moreover, we show that coupling to SIMP/STT3B can be used to foster MHC I presentation of a selected peptide, here the ovalbumin peptide SIINFEKL. These data yield novel insights into relations between the cell proteome and the MHC I immunopeptidome. They suggest that the contribution of a given protein to the MHC I immunopeptidome results from the interplay of at least three factors: the presence of degrons (degradation signals), the tendency of the protein to misfold and its subcellular localization. Furthermore, they indicate that substrates of the ER-associated degradation pathway may have a prominent imprint on the MHC I self-immunopeptidome.

Data from Proteogenomics Uncovers a Vast Repertoire of Shared Tumor-Specific Antigens in Ovarian Cancer

High-grade serous ovarian cancer (HGSC), the principal cause of death from gynecologic malignanci... more High-grade serous ovarian cancer (HGSC), the principal cause of death from gynecologic malignancies in the world, has not significantly benefited from advances in cancer immunotherapy. Although HGSC infiltration by lymphocytes correlates with superior survival, the nature of antigens that can elicit anti-HGSC immune responses is unknown. The goal of this study was to establish the global landscape of HGSC tumor-specific antigens (TSA) using a mass spectrometry pipeline that interrogated all reading frames of all genomic regions. In 23 HGSC tumors, we identified 103 TSAs. Classic TSA discovery approaches focusing only on mutated exonic sequences would have uncovered only three of these TSAs. Other mutated TSAs resulted from out-of-frame exonic translation (n = 2) or from noncoding sequences (n = 7). One group of TSAs (n = 91) derived from aberrantly expressed unmutated genomic sequences, which were not expressed in normal tissues. These aberrantly expressed TSAs (aeTSA) originated primarily from nonexonic sequences, in particular intronic (29%) and intergenic (22%) sequences. Their expression was regulated at the transcriptional level by variations in gene copy number and DNA methylation. Although mutated TSAs were unique to individual tumors, aeTSAs were shared by a large proportion of HGSCs. Taking into account the frequency of aeTSA expression and HLA allele frequencies, we calculated that, in Caucasians, the median number of aeTSAs per tumor would be five. We conclude that, in view of their number and the fact that they are shared by many tumors, aeTSAs may be the most attractive targets for HGSC immunotherapy.

The impact of hypomethylation on the immunopeptidome of acute myeloid leukemia

Peer reviewe

The tumor-specific antigens landscape in acute myeloid leukemia

In theory, tumor-specific antigens (TSAs) represent ideal targets for cancer immunotherapy, but n... more In theory, tumor-specific antigens (TSAs) represent ideal targets for cancer immunotherapy, but none have been identified in acute myeloid leukemia (AML) so far. We have recently designed a proteog-enomic approach allowing the identification of MHC class I-associated peptides deriving from any reading frame of all genomic regions (not only from exons). Using this approach, we could identify 82 TSAs from 18 primary human AML samples. All these TSAs derived from unmutated transcripts which were aberrantly expressed by allegedly non-coding regions of the genome (that would have been missed by conventional exome-based approaches). In agreement with previous reports showing that high intron retention is a key feature in AML, we found that introns were the main source of TSAs (54.8%). The TSAs were presented by 24 different HLA allotypes, together covering 98,04% of the world population. The examination of the expression of the RNAs coding for the TSAs showed that most of them (68%) were expressed by at least 50% of AML samples in the “The Cancer Genome Atlas” (TCGA) cohort while all of them were either expressed at very low levels or not expressed at all in normal tissues (from the “Genotype-Tissue Expression” (GTEx) project). We have yet to discover the specific epigenetic changes leading to TSA expression in cancer cells. Meanwhile, we propose that vaccination against ab-errantly expressed TSAs could be used to treat a vast majority of patients, with minimal risks of collateral damage to healthy normal tissues.Peer reviewe

Transposable elements (TE) are repetitive sequences representing ∼45% of the human and mouse geno... more Transposable elements (TE) are repetitive sequences representing ∼45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTEC). In this study, we investigated the role of transposable elements (TE), which are highly expressed by medullary thymic epithelial cells (mTEC), on T-cell development in the thymus. We performed multi-omic analyses of TEs in human and mouse thymic cells to elucidate their role in T cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TEs interact with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDC). In mTECs, TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and RELB) and generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and ...

Abstract 2987: BamQuery: a new proteogenomic tool to explore the immunopeptidome and prioritize actionable tumor antigens

Cancer Research

MHC class I-associated peptides (MAPs), collectively referred to as the immunopeptidome, have a p... more MHC class I-associated peptides (MAPs), collectively referred to as the immunopeptidome, have a pivotal role in cancer immunosurveillance. While MAPs were long thought to be solely generated by the degradation of canonical proteins, recent advances in the field of proteogenomics (genomically-informed proteomics) evidenced that ∼10% of them originate from allegedly noncoding genomic sequences. Among these sequences, endogenous retroelements (EREs) are under intense scrutiny as a possible source of actionable tumor antigens (TAs). With the increasing number of cancer-oriented immunopeptidomic and proteogenomic studies comes the need to accurately attribute an RNA expression level to each MAP identified by mass-spectrometry. Here, we introduce BamQuery (BQ), a computational tool to attribute an exhaustive RNA expression to MAPs of any genomic origin (exon, intron, UTR, intergenic) from bulk and single-cell RNA-sequencing data. By using BQ on large datasets of published MAPs identified ...

Induced pluripotent stem cells display a distinct set of MHC I-associated peptides shared by human cancers

Cell Reports

REVIEW A comprehensive map of the mTOR signaling network

Received 13.7.10; accepted 12.11.10 The mammalian target of rapamycin (mTOR) is a central regulat... more Received 13.7.10; accepted 12.11.10 The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation. mTOR signaling is frequently dysregulated in oncogenic cells, and thus an attractive target for anticancer therapy. Using CellDesigner, a modeling support software for graphical notation, we present herein a comprehensivemap of themTOR signaling network, which includes 964 species connected by 777 reactions. The map complies with both the systems biology markup language (SBML) and graphical notation (SBGN) for computational analysis and graphical representation, respectively. As captured in the mTOR map, we review and discuss our current understanding of the mTOR signaling network and highlight the impact of mTOR feedback and crosstalk regulations on drug-based cancer therapy. This

The MHC I Immunopeptidome Is Moulded by the Transcriptome and Conceals a Tissue-Specific Signature

Blood, 2007

Background: Cell surface MHC I molecules are associated with self peptides that are collectively ... more Background: Cell surface MHC I molecules are associated with self peptides that are collectively referred to as the self MHC I immunopeptidome (sMII). The sMII plays vital roles: it shapes the repertoire of developing thymocytes, transmits survival signals to mature CD8 T cells, amplifies responses against intracellular pathogens, allows immunosurveillance of neoplastic cells, and influences mating preferences in mice. Despite the tremendous importance of the sMII, very little is known on its genesis and molecular composition. Methodology/Principal Findings: We developed a novel high-throughput mass spectrometry approach that yields an accurate definition of the nature and relative abundance of unlabeled peptides presented by MHC I molecules. Two major points emerged from a comprehensive analysis of the sMII of primary mouse thymocytes: the sMII is enriched in peptides derived from highly abundant transcripts; and the sMII conceals a tissue-specific signature that emanates from abou...

International Immunology, 2005

Genome Biology

MHC-I-associated peptides deriving from non-coding genomic regions and mutations can generate tum... more 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.

Table S4 from Proteogenomics Uncovers a Vast Repertoire of Shared Tumor-Specific Antigens in Ovarian Cancer

Table S4

The tumor-specific antigen landscape of acute myeloid leukemia

Molecular Immunology

Single UM171‐Expanded Cord Blood Transplants Support Robust T‐Cell Reconstitution with Low Rates of Severe Infections

STEM CELLS Translational Medicine, 2020

7 Introduction Rapid T cell reconstitution following hematopoietic stem cell transplantation is e... more 7 Introduction Rapid T cell reconstitution following hematopoietic stem cell transplantation is essential for protection against infections and has been associated with lower incidence of chronic graftvs-host disease (cGVHD), relapse, and transplant-related mortality (TRM). Although cord blood (CB) transplants are associated with lower rates of cGVHD and relapse, their low stem cell content results in slower immune reconstitution and higher risk of graft failure, severe infections, and TRM. Objective Recently, results of a phase I/II trial revealed that single UM171-expanded CB transplant allowed the use of smaller CB units without compromising engraftment. The present study assessed T cell reconstitution and immune function in patients transplanted with UM171-expanded CB grafts. Methods We performed a retrospective analysis of a cohort of 20 patients treated with UM171-expanded CB and compared it to a contemporary cohort of 12 patients treated in the same institution who received unmanipulated CB transplant with similar conditioning regimens. We used flow cytometry and T cell receptor (TCR) sequencing to evaluate T cell reconstitution, and we used virus-specific ELISpot assays to evaluate T cell function in the first year post-transplantation. We also categorized infectious events according to the definitions of infection severity in the “Bone and Marrow Transplant Clinical Trials Network Technical Manual of Procedures,” Version 3.0, and report the mean cumulative count of infectious events for each cohort. Results While median T cell dose in graft was at least 2 to 3 times lower for the cohort of patients treated with UM171-expanded CB, numbers and phenotype of T cells at 3, 6, and 12 months post-transplant were similar between the two cohorts. TCR sequencing analyses revealed that UM171 patients had greater T cell diversity and higher numbers of clonotypes at 12 months post-transplant. This was associated with higher counts of naïve T cells and recent thymic emigrants, suggesting active thymopoiesis and correlating with the demonstration that UM171 expands common lymphoid progenitors in vitro. UM171 patients also showed rapid virus-specific T cell reactivity. Most importantly, UM171 patients showed a significantly reduced incidence of severe infections, especially for bacterial and viral infections (Figure 1). Discussion These results suggest that UM171 patients benefit from rapid T cell reconstitution, which likely contributes to the absence of moderate/severe cGVHD, infection-related mortality and late TRM observed in this cohort. STEM CELLS TRANSLATIONAL MEDICINE | StemCellsTM.com © AlphaMed Press 2020 CLINICAL TRIALS— HEMATOPOIETIC STEM CELL THERAPY

ArXiv, 2018

Representation learning is at the heart of what makes deep learning effective. In this work, we i... more Representation learning is at the heart of what makes deep learning effective. In this work, we introduce a new framework for representation learning that we call "Holographic Neural Architectures" (HNAs). In the same way that an observer can experience the 3D structure of a holographed object by looking at its hologram from several angles, HNAs derive Holographic Representations from the training set. These representations can then be explored by moving along a continuous bounded single dimension. We show that HNAs can be used to make generative networks, state-of-the-art regression models and that they are inherently highly resistant to noise. Finally, we argue that because of their denoising abilities and their capacity to generalize well from very few examples, models based upon HNAs are particularly well suited for biological applications where training examples are rare or noisy.

Transplantation and Cellular Therapy, 2021

, UM171-expanded cord blood transplants support robust T cell reconstitution with low rates of se... more , UM171-expanded cord blood transplants support robust T cell reconstitution with low rates of severe infections,

Most Non-Canonical Proteins Uniquely Populate the Proteome or Immunopeptidome

SSRN Electronic Journal, 2020

Combining RNA-sequencing, ribosome profiling, and mass spectrometry, we elucidate the contributio... more Combining RNA-sequencing, ribosome profiling, and mass spectrometry, we elucidate the contribution of non-canonical translation to the proteome and MHC class I immunopeptidome. Remarkably, of 14,498 proteins identified in three human B cell lymphomas, 2,503 are unannotated. Of these, 28% are new isoforms, and 72% are cryptic proteins encoded by ostensibly noncoding regions (60%) or frameshifted canonical genes (12%). Cryptic proteins are translated as efficiently as canonical proteins, have more predicted disordered residues and lower stability and critically, generate MHC-I peptides 5-fold more efficiently per translation event. Translating 5’ “untranslated” regions selectively hindered downstream translation of genes involved in transcription, translation and anti-viral responses. Novel protein isoforms showed strong enrichment for signaling pathways dysregulated in cancer. Only a small fraction of cryptic proteins detected in the proteome contribute to the MHC-I immunopeptidome, demonstrating the high preferential access of cryptic defective ribosomal products to the class I pathway.

MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and neo... more MHC-I associated peptides (MAPs) play a central role in the elimination of virus-infected and neoplastic cells by CD8 T cells. However, accurately predicting the MAP repertoire remains difficult, because only a fraction of the transcriptome generates MAPs. In this study, we investigated whether codon arrangement (usage and placement) regulates MAP biogenesis. We developed an artificial neural network called Codon Arrangement MAP Predictor (CAMAP), predicting MAP presentation solely from mRNA sequences flanking the MAP coding regions, while excluding the MAP-coding codons per se. CAMAP predictions were significantly more accurate when using codon sequences than amino acid sequences. Furthermore, predictions were independent of mRNA expression and MAP binding affinity to MHC-I molecules, and applied to several cell types and species. Combining MAP binding affinity, transcript expression level and CAMAP scores was particularly useful to ameliorate predictions of MAP derived from lowly ...

Genome Medicine, 2020

Background Endogenous retroelements (EREs) constitute about 42% of the human genome and have been... more Background Endogenous retroelements (EREs) constitute about 42% of the human genome and have been implicated in common human diseases such as autoimmunity and cancer. The dominant paradigm holds that EREs are expressed in embryonic stem cells (ESCs) and germline cells but are repressed in differentiated somatic cells. Despite evidence that some EREs can be expressed at the RNA and protein levels in specific contexts, a system-level evaluation of their expression in human tissues is lacking. Methods Using RNA sequencing data, we analyzed ERE expression in 32 human tissues and cell types, including medullary thymic epithelial cells (mTECs). A tissue specificity index was computed to identify tissue-restricted ERE families. We also analyzed the transcriptome of mTECs in wild-type and autoimmune regulator (AIRE)-deficient mice. Finally, we developed a proteogenomic workflow combining RNA sequencing and mass spectrometry (MS) in order to evaluate whether EREs might be translated and gene...