Publications of Grégory Ehx
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See detailHigh proportion of terminally-differentiated regulatory T cells after allogeneic hematopoietic stem cell transplantation
Ritacco, Caroline ULiege; Ehx, Grégory ULiege; GREGOIRE, Céline ULiege et al

in Bone Marrow Transplantation (in press)

It is now well-established that regulatory T cells (Treg) represent a heterogeneous group of CD4+ T cells. Previous studies have demonstrated that Treg homeostasis was impacted by allogeneic hematopoietic ... [more ▼]

It is now well-established that regulatory T cells (Treg) represent a heterogeneous group of CD4+ T cells. Previous studies have demonstrated that Treg homeostasis was impacted by allogeneic hematopoietic cell transplantation (allo-HCT) and particularly so in patients with chronic graft-versus-host disease (GVHD). Here, we first assessed the ability of various Treg subsets to phosphorylate STAT5 in response to IL-2 or IL-7 stimulation in vitro. We then compared the frequencies of different Treg subtypes in healthy controls as well as in allo-HCT patients with or without chronic GVHD. The highest phosphorylated STAT5 (pSTAT5) signal in response to IL-2 was observed in the CD45RO+CD26−CD39+HLA-DR+ Treg fraction. In contrast, naive Treg were mostly less susceptible to IL-2 stimulation in vitro. Following IL-7 stimulation, most Treg subpopulations upregulated pSTAT5 expression but to a lesser extent than conventional T cells. Compared to healthy controls, allo-HCT patients had lower frequencies of the naive CD45RAbrightCD26+ Treg subpopulation but higher frequencies of the most differentiated memory CD45RO+CD26−CD39+ Treg subpopulations. Further, unbiased analysis revealed that six Treg clusters characterized by high expression of CD25, HLA-DR, and ICOS were significantly more frequent in patients with no or with limited chronic GVHD than in those with moderate/severe chronic GVHD. [less ▲]

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See detailComprehensive analysis of the immunomodulatory effects of rapamycin on human T cells in graft-versus-host disease prophylaxis
Ehx, Grégory ULiege; Ritacco, Caroline ULiege; HANNON, Muriel ULiege et al

in American Journal of Transplantation (in press)

Graft-versus-host disease (GVHD) is a major cause of toxicity after allogeneic hematopoietic cell transplantation (allo-HCT). While rapamycin (RAPA) is commonly used in GVHD prophylaxis in combination ... [more ▼]

Graft-versus-host disease (GVHD) is a major cause of toxicity after allogeneic hematopoietic cell transplantation (allo-HCT). While rapamycin (RAPA) is commonly used in GVHD prophylaxis in combination with a calcineurin inhibitor (CNI), the understanding of its mechanism of action on human T cells is still incomplete. Here, we performed an extensive analysis of RAPA effects on human T cells in a humanized mouse model of GVHD, in ex-vivo T-cell cultures and in patients given RAPA plus tacrolimus as GVHD prophylaxis after non-myeloablative allo-HCT. We demonstrate that RAPA mitigates GVHD by decreasing T-cell engraftment and differentiation, inhibiting CD8+ T-cell activation and increasing the long-term IL-2 secretion, thereby supporting regulatory T-cell (Treg) proliferation. In contrast, graft-versus-leukemia effects were not abrogated, as RAPA-treated T cells had increased resistance to apoptosis and retained their effector function and proliferative capacity upon re-stimulation. Importantly, we found that RAPA impact on Treg and CD8+ T cells was closely dependent upon IL-2 signaling and that therapeutic options interfering with IL-2, such as calcineurin inhibitors, antagonize the IL-2-dependent promotion of Treg mediated by RAPA. Our results suggest that RAPA immunological efficacy could be improved in combination with drugs having possible synergistic effects such as the hypomethylating agent 5-azacytidine. [less ▲]

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See detailBamQuery: A new proteogenomic tool to explore the immunopeptidome and validate tumor‐specific antigens
Ruiz, Maria Virginia; Apavaloaei, Anca; Zhao, Qingchuan et al

Conference (2021, September 04)

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 ... [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 MAPs originate from allegedly noncoding genomic sequences. Among these sequences, the endogenous retroelements (EREs) are under intense scrutiny as a possible source of cancer-specific antigens (TSAs). 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 count all reads able to code for any MAP in any RNA-seq data chosen by the user, and to annotate each MAP with all available biological features. Using BQ, we found that most canonical MAPs can derive from an average of two different genomic regions, whereas most tested ERE-derived MAPs can be generated by numerous (median of 210) different genomic regions and RNA transcripts. We show that published ERE MAPs considered as TSA candidates can be coded by numerous other genomic regions than those previously studied, resulting in high undetected expression in normal tissues. We also show that some mutated neoantigens previously published as presumably specific anti-cancer targets can in fact be generated by other non-mutated, non-coding, widely expressed RNA-seq reads in normal tissues. We therefore conclude that BQ could become an essential tool in any TSA-identification/validation pipelines in the near future. [less ▲]

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See detailBamQuery: A new proteogenomic tool to explore the immunopeptidome and validate tumor‐specific antigens
Ruiz, Maria Virginia; Apavaloaei, Anca; Zhao, Qingchuan et al

in European Journal of Immunology (2021, August), 51(S1), 60

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 ... [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 MAPs originate from allegedly noncoding genomic sequences. Among these sequences, the endogenous retroelements (EREs) are under intense scrutiny as a possible source of cancer-specific antigens (TSAs). 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 count all reads able to code for any MAP in any RNA-seq data chosen by the user, and to annotate each MAP with all available biological features. Using BQ, we found that most canonical MAPs can derive from an average of two different genomic regions, whereas most tested ERE-derived MAPs can be generated by numerous (median of 210) different genomic regions and RNA transcripts. We show that published ERE MAPs considered as TSA candidates can be coded by numerous other genomic regions than those previously studied, resulting in high undetected expression in normal tissues. We also show that some mutated neoantigens previously published as presumably specific anti-cancer targets can in fact be generated by other non-mutated, non-coding, widely expressed RNA-seq reads in normal tissues. We therefore conclude that BQ could become an essential tool in any TSA-identification/validation pipelines in the near future. [less ▲]

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See detailAtypical acute myeloid leukemia-specific transcripts generate shared and immunogenic MHC class-I-associated epitopes
Ehx, Grégory ULiege; Larouche, Jean-David; Durette, Chantal et al

in Immunity (2021), 54(4), 737-752

Acute myeloid leukemia (AML) has not benefited from innovative immunotherapies, mainly because of the lack of actionable immune targets. Using an original proteogenomic approach, we analyzed the major ... [more ▼]

Acute myeloid leukemia (AML) has not benefited from innovative immunotherapies, mainly because of the lack of actionable immune targets. Using an original proteogenomic approach, we analyzed the major histocompatibility complex class I (MHC class I)-associated immunopeptidome of 19 primary AML samples and identified 58 tumor-specific antigens (TSAs). These TSAs bore no mutations and derived mainly (86%) from supposedly non-coding genomic regions. Two AML-specific aberrations were instrumental in the biogenesis of TSAs, intron retention, and epigenetic changes. Indeed, 48% of TSAs resulted from intron retention and translation, and their RNA expression correlated with mutations of epigenetic modifiers (e.g., DNMT3A). AML TSA-coding transcripts were highly shared among patients and were expressed in both blasts and leukemic stem cells. In AML patients, the predicted number of TSAs correlated with spontaneous expansion of cognate T cell receptor clonotypes, accumulation of activated cytotoxic T cells, immunoediting, and improved survival. These TSAs represent attractive targets for AML immunotherapy. [less ▲]

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See detailItacitinib prevents xenogeneic GVHD in humanized mice
Courtois, Justine ULiege; Ritacco, Caroline ULiege; DUBOIS, Sophie ULiege et al

in Bone Marrow Transplantation (2021)

We assessed the impact of the Janus Kinase (JAK) 1 inhibitor itacitinib on xenogeneic graft-versus-host disease (xGVHD). XGVHD was induced by i.v. injection 20x106 human peripheral blood mononuclear cells ... [more ▼]

We assessed the impact of the Janus Kinase (JAK) 1 inhibitor itacitinib on xenogeneic graft-versus-host disease (xGVHD). XGVHD was induced by i.v. injection 20x106 human peripheral blood mononuclear cells (hPBMC) in NSG mice on day 0. Itacitinib (3 mg, ≈ 120 mg/kg) or methylcellulose was administered by force-feeding twice a day from day 3 to day 28. Mice were followed for xGVHD score and survival. In addition, human T-cell engraftment and as well as human T-cell subtypes were monitored in blood on days 14, 21 and 28 after transplantation. We observed that itacitinib-treated mice had significantly longer survival than control mice (median 45 versus 33 days; P<0.001). Further, they also had lower absolute numbers of human CD4+ T cells on days 21 and 28 after transplantation as well as of human CD8+ T cells on days 14, 21 and 28 after transplantation. In addition, itacitinib-treated mice had higher frequencies of human regulatory T cells (Treg) on days 21 and 28 after transplantation. In summary, our data indicate that itacitinib decreases human T-cell engraftment, increases Treg frequencies and attenuates xGVHD in NSG mice transplanted with hPBMC. [less ▲]

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See detailPredictors of neutralizing antibody response to BNT162b2 vaccination in allogeneic hematopoietic stem cell transplant recipients.
Canti, Lorenzo ULiege; Humblet-Baron, Stéphanie; Desombere, Isabelle et al

in Journal of hematology & oncology (2021), 14(1), 174

BACKGROUND: Factors affecting response to SARS-CoV-2 mRNA vaccine in allogeneic hematopoietic stem cell transplantation (allo-HCT) recipients remain to be elucidated. METHODS: Forty allo-HCT recipients ... [more ▼]

BACKGROUND: Factors affecting response to SARS-CoV-2 mRNA vaccine in allogeneic hematopoietic stem cell transplantation (allo-HCT) recipients remain to be elucidated. METHODS: Forty allo-HCT recipients were included in a study of immunization with BNT162b2 mRNA vaccine at days 0 and 21. Binding antibodies (Ab) to SARS-CoV-2 receptor binding domain (RBD) were assessed at days 0, 21, 28, and 49 while neutralizing Ab against SARS-CoV-2 wild type (NT50) were assessed at days 0 and 49. Results observed in allo-HCT patients were compared to those obtained in 40 healthy adults naive of SARS-CoV-2 infection. Flow cytometry analysis of peripheral blood cells was performed before vaccination to identify potential predictors of Ab responses. RESULTS: Three patients had detectable anti-RBD Ab before vaccination. Among the 37 SARS-CoV-2 naive patients, 20 (54%) and 32 (86%) patients had detectable anti-RBD Ab 21 days and 49 days postvaccination. Comparing anti-RBD Ab levels in allo-HCT recipients and healthy adults, we observed significantly lower anti-RBD Ab levels in allo-HCT recipients at days 21, 28 and 49. Further, 49% of allo-HCT patients versus 88% of healthy adults had detectable NT50 Ab at day 49 while allo-HCT recipients had significantly lower NT50 Ab titers than healthy adults (P = 0.0004). Ongoing moderate/severe chronic GVHD (P < 0.01) as well as rituximab administration in the year prior to vaccination (P < 0.05) correlated with low anti-RBD and NT50 Ab titers at 49 days after the first vaccination in multivariate analyses. Compared to healthy adults, allo-HCT patients without chronic GVHD or rituximab therapy had comparable anti-RBD Ab levels and NT50 Ab titers at day 49. Flow cytometry analyses before vaccination indicated that Ab responses in allo-HCT patients were strongly correlated with the number of memory B cells and of naive CD4(+) T cells (r > 0.5, P < 0.01) and more weakly with the number of follicular helper T cells (r = 0.4, P = 0.01). CONCLUSIONS: Chronic GVHD and rituximab administration in allo-HCT recipients are associated with reduced Ab responses to BNT162b2 vaccination. Immunological markers could help identify allo-HCT patients at risk of poor Ab response to mRNA vaccination. TRIAL REGISTRATION: The study was registered at clinicaltrialsregister.eu on 11 March 2021 (EudractCT # 2021-000673-83). [less ▲]

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See detailPtcy Prevents Xenogeneic Gvhd without Abrogating Gvl Effects
Ritacco, Caroline ULiege; Ehx, Grégory ULiege; Canti, Lorenzo ULiege et al

in Biology of Blood and Marrow Transplantation (2020, March 01), 26(3), 168

Background Post-transplant administration of high-dose cyclophosphamide (PTCy) is one of the most efficient way to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic cell ... [more ▼]

Background Post-transplant administration of high-dose cyclophosphamide (PTCy) is one of the most efficient way to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). However, the impact of PTCy on immune-mediated graft-versus-leukemia (GvL) effects has remained debated. Here, we investigated the impact of PTCy administration on xenogeneic GVHD and allogeneic GvL effects in two humanized mouse models. Impact of PTCy on xGVHD A single i.p. injection of cyclophosphamide (100 mg/kg) 3 days after infusion of 2 × 107 human PBMC in NSG mice significantly delayed xGVHD (64 vs 43 days, P < 0.0001). However, xGVHD was not abrogated and the majority of treated mice eventually succumbed from xGVHD. On day 21 after PBMC infusion, (human) blood T-cell counts were significantly lower in PTCy than in control mice (P = 0.0028) while the proportions of KI67+ CD4+ and CD4+ T cells were similar. Interestingly, at that time point the frequency of Treg in the blood was significantly higher in PTCy than in control mice (12.9 vs 4.3 %, P = 0.03). In further analyses, we compared human cells recovered from mouse blood and organs on day 6 after PBMC infusion (60 hours after PTCy in PTCy-treated mice). In comparison to untreated mice, PTCy mice had a dramatically lower proportion of KI67+ T cells as well as a much higher proportion of CD4+ apoptotic T cells. Treg numbers in the peripheral blood were also significantly lower in PTCy than in control mice. Looking at the bone marrow and other xGVHD target organs, PTCy-treated mice had a lower proportion of proliferative (i.e. KI67+) CD4+ T cells as well as of proliferative Tregs. Impact of PTCy on GvL effects The impact of PTCy on GvL effects was assessed in NSG-HLA-A2/HHD mice (a strain of NSG mice that express in addition to mouse MHC, the human HLA-A0201). All mice were i.v. injected with the human (HLA-A0201) AML cell line THP-1 transfected with the luciferase gene on day 0, while a second injection of THP-1 cells was administered on day 5. Four groups of mice were compared, a group of mice given only THP-1 cells, a second group given THP-1 cells and PTCy on day 3, a third group given THP-1 cells and human PBMC from a non HLA-A2 donor, and a last group of mice given THP-1 cells, PTCy and human PBMC from the same non HLA-A2 donor. On day 34, none of the THP-1+ PBMC mice had detectable tumors while THP-1 + PTCy + PBMC mice had detectable tumors but to a lesser extent that THP-1 only mice or THP-1+PTCy mice. The best survival was observed in THP-1+PTCy+PBMC mice while THP-1+PBMC mice died from xGVHD whereas THP-1+PTCy as well as THP-1 mice died from leukemia. Conclusions These results suggest that PTCy prevents xGVHD by depleting proliferative T cells and favoring the recovery of Treg. Further, GvL effects (although decreased) were not abrogated by PTCy. [less ▲]

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See detailMajor multilevel molecular divergence between THP-1 cells from different biorepositories
Noronha, Nandita; Ehx, Grégory ULiege; Meunier, Marie-Christine et al

in International Journal of Cancer (2020), 147(7), 2000-2006

The THP-1 cell line is broadly used as a model for acute myeloid leukemia (AML) with MLL fusion and to study monocyte differentiation and function. We studied THP-1 cells obtained from two major ... [more ▼]

The THP-1 cell line is broadly used as a model for acute myeloid leukemia (AML) with MLL fusion and to study monocyte differentiation and function. We studied THP-1 cells obtained from two major biorepositories. The two cell lines were closely related with a percentage match of short tandem repeat (STR) profiles ranging from 93.75% to 100%, depending on the algorithm used. Nevertheless, we found that the two cell lines presented discordant HLA type, cytogenetic aberrations and AML-related gene expression (including critical targets of MLL fusion). These discrepancies resulted mainly from loss of heterozygosity (LOH) involving five chromosomal regions. In view of their aberrant expression of key "leukemia" genes (e.g., LIN28B, MEIS1 and SPARC), we argue that one of the THP-1 cell lines may not be a reliable model for studying leukemia. Their defective expression of HLA molecules and abnormal adhesion properties is also a caveat for studies of antigen presentation. In a more general perspective, our findings show that seemingly minor discrepancies in STR profiles among cell lines may be the sign of major genetic drift, of sufficient magnitude to affect the reliability of cell line-based research. [less ▲]

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See detailMCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents.
Bolomsky, Arnold; Vogler, Meike; Köse, Murat Cem ULiege et al

in Journal of hematology & oncology (2020), 13(1), 173

Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member ... [more ▼]

Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis. [less ▲]

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See detailWidespread and tissue-specific expression of endogenous retroelements in human somatic tissues
Larouche, Jean-David; Trofimov, Assya; Hesnard, Leslie et al

in Genome Medicine (2020), 12(1),

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 ... [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 generate MHC I-associated peptides (MAP) in B-lymphoblastoid cell lines (B-LCL) from 16 individuals. Results: We report that all human tissues express EREs, but the breadth and magnitude of ERE expression are very heterogeneous from one tissue to another. ERE expression was particularly high in two MHC I-deficient tissues (ESCs and testis) and one MHC I-expressing tissue, mTECs. In mutant mice, we report that the exceptional expression of EREs in mTECs was AIRE-independent. MS analyses identified 103 non-redundant ERE-derived MAPs (ereMAPs) in B-LCLs. These ereMAPs preferentially derived from sense translation of intronic EREs. Notably, detailed analyses of their amino acid composition revealed that ERE-derived MAPs presented homology to viral MAPs. Conclusions: This study shows that ERE expression in somatic tissues is more pervasive and heterogeneous than anticipated. The high and diversified expression of EREs in mTECs and their ability to generate MAPs suggest that EREs may play an important role in the establishment of self-tolerance. The viral-like properties of ERE-derived MAPs suggest that those not expressed in mTECs can be highly immunogenic. [less ▲]

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See detailThe impact of hypomethylation on the immunopeptidome of acute myeloid leukemia.
Ehx, Grégory ULiege; Noronha, Nandita; Vincent, Krystel et al

Conference (2019, September 18)

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See detailThe tumor-specific antigens landscape in acute myeloid leukemia
Ehx, Grégory ULiege

Conference (2019, May 31)

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 ... [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. [less ▲]

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See detailThe tumor-specific antigens landscape in acute myeloid leukemia
Ehx, Grégory ULiege; Vincent, Krystel; Larouche, Jean-David et al

Poster (2019, May 31)

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 ... [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. [less ▲]

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See detailDiscovery and characterization of actionable tumor antigens
Ehx, Grégory ULiege; Perreault, Claude

in Genome Medicine (2019), 11(1),

The nature of the tumor antigens that are detectable by T cells remains unclear. In melanoma, T cells were shown to react against major histocompatibility complex (MHC)-associated peptides (MAPs) that are ... [more ▼]

The nature of the tumor antigens that are detectable by T cells remains unclear. In melanoma, T cells were shown to react against major histocompatibility complex (MHC)-associated peptides (MAPs) that are derived from exonic mutations. A recent multi-omic study of hepatocellular carcinomas suggests, however, that mutated exonic MAPs were exceedingly rare, bringing the accuracy of the current methods for antigen identification into question and demonstrating the importance of broadening tumor-antigen discovery efforts. [less ▲]

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See detailIn Vitro Th17-Polarized Human CD4(+) T Cells Exacerbate Xenogeneic Graft-versus-Host Disease.
Delens, Loïc ULiege; Ehx, Gregory ULiege; SOMJA, Joan ULiege et al

in Biology of Blood and Marrow Transplantation (2019), 25

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. The role of Th17 cells in its pathophysiology remains a matter of debate. In this ... [more ▼]

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. The role of Th17 cells in its pathophysiology remains a matter of debate. In this study, we assessed whether enrichment of human peripheral blood mononuclear cells (PBMCs) with in vitro Th17-polarized CD4(+) T cells would exacerbate xenogeneic GVHD (xGVHD) into NOD-scid IL-2Rgamma null (NSG) mice. Naive human CD4(+) T cells were stimulated under Th17-skewing conditions for 8 to 10 days and then coinjected in NSG mice with fresh PBMCs from the same donor. We observed that Th17-polarized cells engrafted and migrated toward xGVHD target organs. They also acquired a double-expressing IL-17A(+)IFNgamma(+) profile in vivo. Importantly, cotransfer of Th17-polarized cells (1x10(6)) with PBMCs (1x10(6)) exacerbated xGVHD compared with transplantation of PBMCs alone (2x10(6)). Furthermore, PBMC cotransfer with Th17-polarized cells was more potent for xGVHD induction than cotransfer with naive CD4(+) T cells stimulated in nonpolarizing conditions (Th0 cells, 1x10(6)+1x10(6) PBMCs) or with Th1-polarized cells (1x10(6)+1x10(6) PBMCs). In summary, our results suggest that human Th17-polarized cells can cooperate with PBMCs and be pathogenic in the NSG xGVHD model. [less ▲]

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See detailComparison of Mesenchymal Stromal Cells From Different Origins for the Treatment of Graft-vs.-Host-Disease in a Humanized Mouse Model.
Grégoire, Céline ULiege; Ritacco, Caroline ULiege; Hannon, Muriel ULiege et al

in Frontiers in Immunology (2019), 10

Mesenchymal stromal cells (MSCs) have potent immunomodulatory properties that make them an attractive tool against graft- vs.-host disease (GVHD). However, despite promising results in phase I/II studies ... [more ▼]

Mesenchymal stromal cells (MSCs) have potent immunomodulatory properties that make them an attractive tool against graft- vs.-host disease (GVHD). However, despite promising results in phase I/II studies, bone marrow (BM-) derived MSCs failed to demonstrate their superiority over placebo in the sole phase III trial reported thus far. MSCs from different tissue origins display different characteristics, but their therapeutic benefits have never been directly compared in GVHD. Here, we compared the impact of BM-, umbilical cord (UC-), and adipose-tissue (AT-) derived MSCs on T-cell function in vitro and assessed their efficacy for the treatment of GVHD induced by injection of human peripheral blood mononuclear cells in NOD-scid IL-2Rgamma(null) HLA-A2/HHD mice. In vitro, resting BM- and AT-MSCs were more potent than UC-MSCs to inhibit lymphocyte proliferation, whereas UC- and AT-MSCs induced a higher regulatory T-cell (CD4(+)CD25(+)FoxP3(+))/T helper 17 ratio. Interestingly, AT-MSCs and UC-MSCs activated the coagulation pathway at a higher level than BM-MSCs. In vivo, AT-MSC infusions were complicated by sudden death in 4 of 16 animals, precluding an analysis of their efficacy. Intravenous MSC infusions (UC- or BM- combined) failed to significantly increase overall survival (OS) in an analysis combining data from 80 mice (hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.32-1.08, P = 0.087). In a sensitivity analysis we also compared OS in control vs. each MSC group separately. The results for the BM-MSC vs. control comparison was HR = 0.63 (95% CI 0.30-1.34, P = 0.24) while the figures for the UC-MSC vs. control comparison was HR = 0.56 (95% CI 0.28-1.10, P = 0.09). Altogether, these results suggest that MSCs from various origins have different effects on immune cells in vitro and in vivo. However, none significantly prevented death from GVHD. Finally, our data suggest that the safety profile of AT-MSC and UC-MSC need to be closely monitored given their pro-coagulant activities in vitro. [less ▲]

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See detailObesity induces metabolic and phenotypic variations in blood monocytes and NK cells.
Colonval, Megan ULiege; Iovino, Margaud ULiege; Esser, Nathalie et al

Poster (2018, June 26)

Introduction : Obesity is recognized as low-grade inflammatory disease, favoring the development of metabolic diseases and cancers. Methods : We investigated by flow cytometry obesity and glucose ... [more ▼]

Introduction : Obesity is recognized as low-grade inflammatory disease, favoring the development of metabolic diseases and cancers. Methods : We investigated by flow cytometry obesity and glucose intolerance effects on monocytes and NK cells in lean and normo-glycemic or (pre)-diabetic obese patients. Results : Monocytes present increased glucose uptake and higher GLUT1 expression in all obese patients. This glucose uptake increase is specifically seen in classical monocytes. In normo-glycemic obese compared to lean patients, CD56dim NK cells are decreased while expression of their activating receptors such as CD16, NKp30, NKG2D and NKp46 is not affected. However CD56high NK cells are increased with obesity and their receptors are differentially modulated according to BMI and glycemia. Discussion : We are assessing monocytes and NK cells activity in different patients groups. We are also doing lipidomics on plasma and PBMC. These experiments will allow us to highlight new correlations between lipidomic, metabolic and immunologic parameters at both systemic and cellular levels. [less ▲]

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