19 results on '"Elkrim Y"'
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2. Adenosine 5' Monophosphate (AMP) and Metacholine Act on Different Sites during Airway Challenge.
- Author
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Michils, A, primary, Elkrim, Y, additional, and Van Muylem, A, additional
- Published
- 2009
- Full Text
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3. Infection history imprints prolonged changes to the epigenome, transcriptome and function of Kupffer cells.
- Author
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Musrati MA, Stijlemans B, Azouz A, Kancheva D, Mesbahi S, Hadadi E, Lebegge E, Ali L, De Vlaminck K, Scheyltjens I, Vandamme N, Zivalj M, Assaf N, Elkrim Y, Ahmidi I, Huart C, Lamkanfi M, Guilliams M, De Baetselier P, Goriely S, Movahedi K, and Van Ginderachter JA
- Abstract
Background and Aims: Liver macrophages fulfill various homeostatic functions and represent an essential line of defense against pathogenic insults. However, it remains unclear whether a history of infectious disease in the liver instructs long-term alterations to the liver macrophage compartment., Methods: We utilized a curable model of parasitic infection invoked by the protozoan parasite Trypanosoma brucei brucei to investigate whether infection history can durably reshape hepatic macrophage identity and function. Employing a combination of fate mapping, single cell CITE-sequencing, single nuclei multiome analysis, epigenomic analysis, and functional assays, we studied the alterations to the liver macrophage compartment during and after the resolution of infection., Results: We show that T. b. brucei infection alters the composition of liver-resident macrophages, leading to the infiltration of monocytes that differentiate into various infection-associated macrophage populations with divergent transcriptomic profiles. Whereas infection-associated macrophages disappear post-resolution of infection, monocyte-derived macrophages engraft in the liver, assume a Kupffer cell (KC)-like profile and co-exist with embryonic KCs in the long-term. Remarkably, the prior exposure to infection imprinted an altered transcriptional program on post-resolution KCs that was underpinned by an epigenetic remodeling of KC chromatin landscapes and a shift in KC ontogeny, along with transcriptional and epigenetic alterations in their niche cells. This reprogramming altered KC functions and was associated with increased resilience to a subsequent bacterial infection., Conclusion: Our study demonstrates that a prior exposure to a parasitic infection induces trained immunity in KCs, reshaping their identity and function in the long-term., Impact and Implications: Although the liver is frequently affected during infections, and despite housing a major population of resident macrophages known as Kupffer cells (KCs), it is currently unclear whether infections can durably alter KCs and their niche cells. Our study provides a comprehensive investigation into the long-term impact of a prior, cured parasitic infection, unveiling long-lasting ontogenic, epigenetic, transcriptomic and functional changes to KCs as well as KC niche cells, which may contribute to KC remodeling. Our data suggest that infection history may continuously reprogram KCs throughout life with potential implications for subsequent disease susceptibility in the liver, influencing preventive and therapeutic approaches., Competing Interests: Declaration of Competing Interest No conflicts of interest to declare, (Copyright © 2024. Published by Elsevier B.V.)
- Published
- 2024
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4. Flt3L therapy increases the abundance of Treg-promoting CCR7 + cDCs in preclinical cancer models.
- Author
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Clappaert EJ, Kancheva D, Brughmans J, Debraekeleer A, Bardet PMR, Elkrim Y, Lacroix D, Živalj M, Hamouda AEI, Van Ginderachter JA, Deschoemaeker S, and Laoui D
- Subjects
- Animals, Mice, Receptors, CCR7, Combined Modality Therapy, CD40 Antigens, Tumor Microenvironment, T-Lymphocytes, Regulatory, Lung Neoplasms drug therapy
- Abstract
Conventional dendritic cells (cDCs) are at the forefront of activating the immune system to mount an anti-tumor immune response. Flt3L is a cytokine required for DC development that can increase DC abundance in the tumor when administered therapeutically. However, the impact of Flt3L on the phenotype of distinct cDC subsets in the tumor microenvironment is still largely undetermined. Here, using multi-omic single-cell analysis, we show that Flt3L therapy increases all cDC subsets in orthotopic E0771 and TS/A breast cancer and LLC lung cancer models, but this did not result in a reduction of tumor growth in any of the models. Interestingly, a CD81
+ migcDC1 population, likely developing from cDC1, was induced upon Flt3L treatment in E0771 tumors as well as in TS/A breast and LLC lung tumors. This CD81+ migcDC1 subset is characterized by the expression of both canonical cDC1 markers as well as migratory cDC activation and regulatory markers and displayed a Treg-inducing potential. To shift the cDC phenotype towards a T-cell stimulatory phenotype, CD40 agonist therapy was administered to E0771 tumor-bearing mice in combination with Flt3L. However, while αCD40 reduced tumor growth, Flt3L failed to improve the therapeutic response to αCD40 therapy. Interestingly, Flt3L+αCD40 combination therapy increased the abundance of Treg-promoting CD81+ migcDC1. Nonetheless, while Treg-depletion and αCD40 therapy were synergistic, the addition of Flt3L to this combination did not result in any added benefit. Overall, these results indicate that merely increasing cDCs in the tumor by Flt3L treatment cannot improve anti-tumor responses and therefore might not be beneficial for the treatment of cancer, though could still be of use to increase cDC numbers for autologous DC-therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Clappaert, Kancheva, Brughmans, Debraekeleer, Bardet, Elkrim, Lacroix, Živalj, Hamouda, Van Ginderachter, Deschoemaeker and Laoui.)- Published
- 2023
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5. Junctional adhesion molecule-A is dispensable for myeloid cell recruitment and diversification in the tumor microenvironment.
- Author
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Kiss M, Lebegge E, Murgaski A, Van Damme H, Kancheva D, Brughmans J, Scheyltjens I, Talebi A, Awad RM, Elkrim Y, Bardet PMR, Arnouk SM, Goyvaerts C, Swinnen J, Nana FA, Van Ginderachter JA, and Laoui D
- Subjects
- Mice, Animals, Tumor Microenvironment genetics, Myeloid Cells metabolism, Monocytes metabolism, Inflammation metabolism, Junctional Adhesion Molecule A
- Abstract
Junctional adhesion molecule-A (JAM-A), expressed on the surface of myeloid cells, is required for extravasation at sites of inflammation and may also modulate myeloid cell activation. Infiltration of myeloid cells is a common feature of tumors that drives disease progression, but the function of JAM-A in this phenomenon and its impact on tumor-infiltrating myeloid cells is little understood. Here we show that systemic cancer-associated inflammation in mice enhanced JAM-A expression selectively on circulating monocytes in an IL1β-dependent manner. Using myeloid-specific JAM-A-deficient mice, we found that JAM-A was dispensable for recruitment of monocytes and other myeloid cells to tumors, in contrast to its reported role in inflammation. Single-cell RNA sequencing revealed that loss of JAM-A did not influence the transcriptional reprogramming of myeloid cells in the tumor microenvironment. Overall, our results support the notion that cancer-associated inflammation can modulate the phenotype of circulating immune cells, and we demonstrate that tumors can bypass the requirement of JAM-A for myeloid cell recruitment and reprogramming., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kiss, Lebegge, Murgaski, Van Damme, Kancheva, Brughmans, Scheyltjens, Talebi, Awad, Elkrim, Bardet, Arnouk, Goyvaerts, Swinnen, Nana, Van Ginderachter and Laoui.)
- Published
- 2022
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6. Efficacy of CD40 Agonists Is Mediated by Distinct cDC Subsets and Subverted by Suppressive Macrophages.
- Author
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Murgaski A, Kiss M, Van Damme H, Kancheva D, Vanmeerbeek I, Keirsse J, Hadadi E, Brughmans J, Arnouk SM, Hamouda AEI, Debraekeleer A, Bosteels V, Elkrim Y, Boon L, Hoves S, Vandamme N, Deschoemaeker S, Janssens S, Garg AD, Vande Velde G, Schmittnaegel M, Ries CH, and Laoui D
- Subjects
- Animals, CD8-Positive T-Lymphocytes, Humans, Mice, Mice, Inbred C57BL, CD40 Antigens agonists, Dendritic Cells metabolism, Macrophages metabolism, Neoplasms metabolism
- Abstract
Agonistic αCD40 therapy has been shown to inhibit cancer progression in only a fraction of patients. Understanding the cancer cell-intrinsic and microenvironmental determinants of αCD40 therapy response is therefore crucial to identify responsive patient populations and to design efficient combinatorial treatments. Here, we show that the therapeutic efficacy of αCD40 in subcutaneous melanoma relies on preexisting, type 1 classical dendritic cell (cDC1)-primed CD8+ T cells. However, after administration of αCD40, cDC1s were dispensable for antitumor efficacy. Instead, the abundance of activated cDCs, potentially derived from cDC2 cells, increased and further activated antitumor CD8+ T cells. Hence, distinct cDC subsets contributed to the induction of αCD40 responses. In contrast, lung carcinomas, characterized by a high abundance of macrophages, were resistant to αCD40 therapy. Combining αCD40 therapy with macrophage depletion led to tumor growth inhibition only in the presence of strong neoantigens. Accordingly, treatment with immunogenic cell death-inducing chemotherapy sensitized lung tumors to αCD40 therapy in subcutaneous and orthotopic settings. These insights into the microenvironmental regulators of response to αCD40 suggest that different tumor types would benefit from different combinations of therapies to optimize the clinical application of CD40 agonists., Significance: This work highlights the temporal roles of different dendritic cell subsets in promoting CD8+ T-cell-driven responses to CD40 agonist therapy in cancer., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
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7. Macrophages are metabolically heterogeneous within the tumor microenvironment.
- Author
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Geeraerts X, Fernández-Garcia J, Hartmann FJ, de Goede KE, Martens L, Elkrim Y, Debraekeleer A, Stijlemans B, Vandekeere A, Rinaldi G, De Rycke R, Planque M, Broekaert D, Meinster E, Clappaert E, Bardet P, Murgaski A, Gysemans C, Nana FA, Saeys Y, Bendall SC, Laoui D, Van den Bossche J, Fendt SM, and Van Ginderachter JA
- Subjects
- Animals, Carcinoma, Lewis Lung genetics, Carcinoma, Lewis Lung immunology, Carcinoma, Lewis Lung metabolism, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung metabolism, Female, Glycolysis, Humans, Lung Neoplasms genetics, Lung Neoplasms immunology, Lung Neoplasms metabolism, Major Histocompatibility Complex, Metabolome, Mice, Mice, Inbred C57BL, Transcriptome, Carcinoma, Lewis Lung pathology, Carcinoma, Non-Small-Cell Lung pathology, Lactates metabolism, Lung Neoplasms pathology, T-Lymphocytes immunology, Tumor Microenvironment, Tumor-Associated Macrophages immunology
- Abstract
Macrophages are often prominently present in the tumor microenvironment, where distinct macrophage populations can differentially affect tumor progression. Although metabolism influences macrophage function, studies on the metabolic characteristics of ex vivo tumor-associated macrophage (TAM) subsets are rather limited. Using transcriptomic and metabolic analyses, we now reveal that pro-inflammatory major histocompatibility complex (MHC)-II
hi TAMs display a hampered tricarboxylic acid (TCA) cycle, while reparative MHC-IIlo TAMs show higher oxidative and glycolytic metabolism. Although both TAM subsets rapidly exchange lactate in high-lactate conditions, only MHC-IIlo TAMs use lactate as an additional carbon source. Accordingly, lactate supports the oxidative metabolism in MHC-IIlo TAMs, while it decreases the metabolic activity of MHC-IIhi TAMs. Lactate subtly affects the transcriptome of MHC-IIlo TAMs, increases L-arginine metabolism, and enhances the T cell suppressive capacity of these TAMs. Overall, our data uncover the metabolic intricacies of distinct TAM subsets and identify lactate as a carbon source and metabolic and functional regulator of TAMs., Competing Interests: Declaration of interests J.A.V.G. received funding from Precirix, Argenx, and Oncurious for projects unrelated to this manuscript and has functioned as a consultant for MSD and Fund+. S.-M.F. has received funding from Bayer, Merck, and Black Belt Therapeutics for different projects and is on the editorial board of Cell Reports. All other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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8. Intrabody Targeting HIF-1α Mediates Transcriptional Downregulation of Target Genes Related to Solid Tumors.
- Author
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Hu Y, Romão E, Vincke C, Brys L, Elkrim Y, Vandevenne M, Liu C, and Muyldermans S
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- Cell Hypoxia genetics, Escherichia coli genetics, Escherichia coli metabolism, Female, Gene Expression Regulation, Neoplastic, HeLa Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit immunology, Protein Domains genetics, Protein Domains immunology, Single-Domain Antibodies genetics, Single-Domain Antibodies immunology, Single-Domain Antibodies metabolism, Transfection, Uterine Cervical Neoplasms pathology, Down-Regulation drug effects, Down-Regulation genetics, Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Single-Domain Antibodies pharmacology, Transcription, Genetic drug effects, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms metabolism
- Abstract
Uncontrolled growth of solid tumors will result in a hallmark hypoxic condition, whereby the key transcriptional regulator of hypoxia inducible factor-1α (HIF-1α) will be stabilized to activate the transcription of target genes that are responsible for the metabolism, proliferation, and metastasis of tumor cells. Targeting and inhibiting the transcriptional activity of HIF-1 may provide an interesting strategy for cancer therapy. In the present study, an immune library and a synthetic library were constructed for the phage display selection of Nbs against recombinant PAS B domain protein (rPasB) of HIF-1α. After panning and screening, seven different nanobodies (Nbs) were selected, of which five were confirmed via immunoprecipitation to target the native HIF-1α subunit. The inhibitory effect of the selected Nbs on HIF-1 induced activation of target genes has been evaluated after intracellular expression of these Nbs in HeLa cells. The dramatic inhibition of both intrabody formats on the expression of HIF-1-related target genes has been confirmed, which indicated the inhibitory efficacy of selected Nbs on the transcriptional activity of HIF-1.
- Published
- 2021
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9. Immunogenicity Risk Profile of Nanobodies.
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Ackaert C, Smiejkowska N, Xavier C, Sterckx YGJ, Denies S, Stijlemans B, Elkrim Y, Devoogdt N, Caveliers V, Lahoutte T, Muyldermans S, Breckpot K, and Keyaerts M
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- Animals, Antibodies blood, Camelids, New World, Cell Proliferation, Coculture Techniques, Cytokines metabolism, Dendritic Cells immunology, Dendritic Cells metabolism, Humans, Membrane Glycoproteins immunology, Receptor, ErbB-2 immunology, Receptors, Immunologic immunology, Single-Domain Antibodies administration & dosage, T-Lymphocytes immunology, Single-Domain Antibodies immunology
- Abstract
Nanobodies (Nbs), the variable domains of camelid heavy chain-only antibodies, are a promising class of therapeutics or in vivo imaging reagents entering the clinic. They possess unique characteristics, including a minimal size, providing fast pharmacokinetics, high-target specificity, and an affinity in the (sub-)nanomolar range in conjunction with an easy selection and production, which allow them to outperform conventional antibodies for imaging and radiotherapeutic purposes. As for all protein theranostics, extended safety assessment and investigation of their possible immunogenicity in particular are required. In this study, we assessed the immunogenicity risk profile of two Nbs that are in phase II clinical trials: a first Nb against Human Epidermal growth factor Receptor 2 (HER2) for PET imaging of breast cancer and a second Nb with specificity to the Macrophage Mannose Receptor (MMR) for PET imaging of tumor-associated macrophages. For the anti-HER2 Nb, we show that only one out of 20 patients had a low amount of pre-existing anti-drug antibodies (ADAs), which only marginally increased 3 months after administering the Nb, and without negative effects of safety and pharmacokinetics. Further in vitro immunogenicity assessment assays showed that both non-humanized Nbs were taken up by human dendritic cells but exhibited no or only a marginal capacity to activate dendritic cells or to induce T cell proliferation. From our data, we conclude that monomeric Nbs present a low immunogenicity risk profile, which is encouraging for their future development toward potential clinical applications., One Sentence Summary: Nanobodies, the recombinant single domain affinity reagents derived from heavy chain-only antibodies in camelids, are proven to possess a low immunogenicity risk profile, which will facilitate a growing number of Nanobodies to enter the clinic for therapeutic or in vivo diagnostic applications., Competing Interests: SD was employed by SD Analytics. ND, MK, and TL hold patents on the use of anti-HER2 and -MMR Nbs for the diagnosis and treatment of cancer and cardiovascular diseases. ND and TL are co-founder of, shareholder of and employed by or consultant for Precirix, a company that uses the anti-HER2 nanobody in radiotherapeutic applications. ND, MK, and TL are co-founder of Abscint who develops the anti-HER2 and anti-MMR Nb tracers for diagnostic purposes. ND has received funding from Boehringer-Ingelheim, Complix, Agenus, Confo Therapeutics, Roche, 121BIO, Agenus, Exevir, and Telix Pharma. MK, TL, ND, and CX have patents on Nb imaging and therapy. TL received honoraria from Precirix (consultant and board member), IBA (scientific advisor), and Institut des Radioéléments (IRE) (scientific advisor). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ackaert, Smiejkowska, Xavier, Sterckx, Denies, Stijlemans, Elkrim, Devoogdt, Caveliers, Lahoutte, Muyldermans, Breckpot and Keyaerts.)
- Published
- 2021
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10. Myeloid tumor necrosis factor and heme oxygenase-1 regulate the progression of colorectal liver metastases during hepatic ischemia-reperfusion.
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Germanova D, Keirsse J, Köhler A, Hastir JF, Demetter P, Delbauve S, Elkrim Y, Verset L, Larbanoix L, Preyat N, Laurent S, Nedospasov S, Donckier V, Van Ginderachter JA, and Flamand V
- Subjects
- Animals, Disease Progression, Kupffer Cells physiology, Male, Mice, Mice, Inbred C57BL, Monocytes physiology, Receptor-Interacting Protein Serine-Threonine Kinases physiology, Colorectal Neoplasms pathology, Heme Oxygenase-1 physiology, Liver blood supply, Liver Neoplasms etiology, Liver Neoplasms secondary, Neoplasm Recurrence, Local etiology, Reperfusion Injury complications, Tumor Necrosis Factor-alpha physiology
- Abstract
The liver ischemia-reperfusion (IR) injury that occurs consequently to hepatic resection performed in patients with metastases can lead to tumor relapse for not fully understood reasons. We assessed the effects of liver IR on tumor growth and the innate immune response in a mouse model of colorectal (CR) liver metastasis. Mice subjected to liver ischemia 2 days after intrasplenic injection of CR carcinoma cells displayed a higher metastatic load in the liver, correlating with Kupffer cells (KC) death through the activation of receptor-interating protein 3 kinase (RIPK3) and caspase-1 and a recruitment of monocytes. Interestingly, the immunoregulatory mediators, tumor necrosis factor-α (TNF-α) and heme oxygenase-1 (HO-1) were strongly upregulated in recruited monocytes and were also expressed in the surviving KC following IR. Using TNF
flox/flox LysMcre/wt mice, we showed that TNF deficiency in macrophages and monocytes favors tumor progression after IR. The antitumor effect of myeloid cell-derived TNF involved direct tumor cell apoptosis and a reduced expression of immunosuppressive molecules such as transforming growth factor-β, interleukin (IL)-10, inducible nitric oxyde synthase (iNOS), IL-33 and HO-1. Conversely, a monocyte/macrophage-specific deficiency in HO-1 (HO-1flox/flox LysMcre/wt ) or the blockade of HO-1 function led to the control of tumor progression post-liver IR. Importantly, host cell RIPK3 deficiency maintains the KC number upon IR, inhibits the IR-induced innate cell recruitment, increases the TNF level, decreases the HO-1 level and suppresses the tumor outgrowth. In conclusion, tumor recurrence in host undergoing liver IR is associated with the death of antitumoral KC and the recruitment of monocytes endowed with immunosuppressive properties. In both of which HO-1 inhibition would reinforce their antitumoral activity., (© 2020 UICC.)- Published
- 2021
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11. IL1β Promotes Immune Suppression in the Tumor Microenvironment Independent of the Inflammasome and Gasdermin D.
- Author
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Kiss M, Vande Walle L, Saavedra PHV, Lebegge E, Van Damme H, Murgaski A, Qian J, Ehling M, Pretto S, Bolli E, Keirsse J, Bardet PMR, Arnouk SM, Elkrim Y, Schmoetten M, Brughmans J, Debraekeleer A, Fossoul A, Boon L, Raes G, van Loo G, Lambrechts D, Mazzone M, Beschin A, Wullaert A, Lamkanfi M, Van Ginderachter JA, and Laoui D
- Subjects
- Animals, Cell Communication immunology, Disease Models, Animal, Female, Humans, Inflammasomes immunology, Inflammasomes metabolism, Interleukin-1beta genetics, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Lymphocytes, Tumor-Infiltrating immunology, Mice, Mice, Knockout, Neoplasms pathology, Neutrophils metabolism, Phosphate-Binding Proteins genetics, Phosphate-Binding Proteins metabolism, T-Lymphocytes, Cytotoxic immunology, Tumor-Associated Macrophages immunology, Interleukin-1beta metabolism, Neoplasms immunology, Neutrophils immunology, Tumor Escape, Tumor Microenvironment immunology
- Abstract
IL1β is a central mediator of inflammation. Secretion of IL1β typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1β in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1β in driving tumor progression in two distinct mouse tumor models. Notably, activation of the inflammasome, caspase-8, as well as the pore-forming proteins GSDMD and mixed lineage kinase domain-like protein in the host were dispensable for the release of intratumoral bioactive IL1β. Inflammasome-independent IL1β release promoted systemic neutrophil expansion and fostered accumulation of T-cell-suppressive neutrophils in the tumor. Moreover, IL1β was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1β allowed intratumoral accumulation of CD8
+ effector T cells that subsequently activated tumor-associated macrophages. Depletion of either CD8+ T cells or macrophages abolished tumor growth inhibition in IL1β-deficient mice, demonstrating a crucial role for CD8+ T-cell-macrophage cross-talk in the antitumor immune response. Overall, these results support a tumor-promoting role for IL1β through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors., (©2020 American Association for Cancer Research.)- Published
- 2021
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12. Therapeutic depletion of CCR8 + tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy.
- Author
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Van Damme H, Dombrecht B, Kiss M, Roose H, Allen E, Van Overmeire E, Kancheva D, Martens L, Murgaski A, Bardet PMR, Blancke G, Jans M, Bolli E, Martins MS, Elkrim Y, Dooley J, Boon L, Schwarze JK, Tacke F, Movahedi K, Vandamme N, Neyns B, Ocak S, Scheyltjens I, Vereecke L, Nana FA, Merchiers P, Laoui D, and Van Ginderachter JA
- Subjects
- Animals, Carcinoma, Lewis Lung genetics, Carcinoma, Lewis Lung immunology, Carcinoma, Lewis Lung metabolism, Combined Modality Therapy, Databases, Genetic, Female, Gene Expression Profiling, Humans, Lung Neoplasms genetics, Lung Neoplasms immunology, Lung Neoplasms metabolism, Lymphocytes, Tumor-Infiltrating metabolism, Melanoma, Experimental genetics, Melanoma, Experimental immunology, Melanoma, Experimental metabolism, Mice, Inbred C57BL, Mice, Knockout, Molecular Targeted Therapy, Phenotype, Programmed Cell Death 1 Receptor metabolism, RNA-Seq, Receptors, CCR8 genetics, Skin Neoplasms genetics, Skin Neoplasms immunology, Skin Neoplasms metabolism, T-Lymphocytes, Regulatory metabolism, Mice, Antineoplastic Agents, Immunological pharmacology, Carcinoma, Lewis Lung therapy, Immune Checkpoint Inhibitors pharmacology, Lung Neoplasms drug therapy, Lymphocyte Depletion, Lymphocytes, Tumor-Infiltrating immunology, Melanoma, Experimental therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors, Receptors, CCR8 deficiency, Skin Neoplasms therapy, T-Lymphocytes, Regulatory immunology
- Abstract
Background: Modulation and depletion strategies of regulatory T cells (Tregs) constitute valid approaches in antitumor immunotherapy but suffer from severe adverse effects due to their lack of selectivity for the tumor-infiltrating (ti-)Treg population, indicating the need for a ti-Treg specific biomarker., Methods: We employed single-cell RNA-sequencing in a mouse model of non-small cell lung carcinoma (NSCLC) to obtain a comprehensive overview of the tumor-infiltrating T-cell compartment, with a focus on ti-Treg subpopulations. These findings were validated by flow cytometric analysis of both mouse (LLC-OVA, MC38 and B16-OVA) and human (NSCLC and melanoma) tumor samples. We generated two CCR8-specific nanobodies (Nbs) that recognize distinct epitopes on the CCR8 extracellular domain. These Nbs were formulated as tetravalent Nb-Fc fusion proteins for optimal CCR8 binding and blocking, containing either an antibody-dependent cell-mediated cytotoxicity (ADCC)-deficient or an ADCC-prone Fc region. The therapeutic use of these Nb-Fc fusion proteins was evaluated, either as monotherapy or as combination therapy with anti-programmed cell death protein-1 (anti-PD-1), in both the LLC-OVA and MC38 mouse models., Results: We were able to discern two ti-Treg populations, one of which is characterized by the unique expression of Ccr8 in conjunction with Treg activation markers. Ccr8 is also expressed by dysfunctional CD4
+ and CD8+ T cells, but the CCR8 protein was only prominent on the highly activated and strongly T-cell suppressive ti-Treg subpopulation of mouse and human tumors, with no major CCR8-positivity found on peripheral Tregs. CCR8 expression resulted from TCR-mediated Treg triggering in an NF-κB-dependent fashion, but was not essential for the recruitment, activation nor suppressive capacity of these cells. While treatment of tumor-bearing mice with a blocking ADCC-deficient Nb-Fc did not influence tumor growth, ADCC-prone Nb-Fc elicited antitumor immunity and reduced tumor growth in synergy with anti-PD-1 therapy. Importantly, ADCC-prone Nb-Fc specifically depleted ti-Tregs in a natural killer (NK) cell-dependent fashion without affecting peripheral Tregs., Conclusions: Collectively, our findings highlight the efficacy and safety of targeting CCR8 for the depletion of tumor-promoting ti-Tregs in combination with anti-PD-1 therapy., Competing Interests: Competing interests: HR and EA are employees of Oncurious NV. PM is a consultant to Oncurious NV., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2021
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13. STAT6 Mediates Footpad Immunopathology in the Absence of IL-12p40 Following Infection of Susceptible BALB/c Mice With Leishmania major .
- Author
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Kauffmann F, Meert E, de Jonge K, Elkrim Y, Hanot Mambres D, Denis O, Muraille E, Magez S, and De Trez C
- Subjects
- Animals, Foot parasitology, Foot pathology, Interleukin-12 Subunit p40 immunology, Leishmania major, Leishmaniasis, Cutaneous parasitology, Leishmaniasis, Cutaneous pathology, Mice, Inbred BALB C, Mice, Knockout, Neutrophils immunology, STAT6 Transcription Factor immunology, Interleukin-12 Subunit p40 genetics, Leishmaniasis, Cutaneous immunology, STAT6 Transcription Factor genetics
- Abstract
Leishmania major ( L. major ) parasites are intracellular parasites belong to the Trypanosomatidae family and are the causative agent of cutaneous leishmaniasis. This disease affects approximately 1.5 million per year worldwide and there is currently no prophylactic vaccine available. L. major is transmitted by the bite of an infected sandfly and has been considered for decades now as a mouse model of choice to identify the factors implicated in T helper (Th)1 and Th2 polarization due to the natural resistance and susceptibility to infection of C57BL/6 and BALB/c mice, respectively. In this study, we refine the role of IL-12p40 cytokine, which is implicated the development of a protective Th1 response, and STAT6, a transcription factor involved in the signaling via detrimental interleukin (IL)-4 and IL-13 associated Th2 cytokines during L. major infection in the BALB/c model. In the absence of STAT6 and IL-12p40 signaling, double knockout (DKO) susceptible BALB/c mice displayed reduced footpad swelling and ulcerative lesion compared to IL-12p40
-/- mice upon L. major infection. Hence, they expressed slower upregulation of keratinocyte markers implicated in the inhibition of wound healing, such as keratin 6a (Krt6a) and Krt16. This coincides with the presence of neutrophils displaying an altered phenotype characterized by a lower expression of surface markers Ly6C, CD11b, and Ly6G. These neutrophils exhibited very lower levels of apoptosis similarly to neutrophils present in resistant STAT6-/- mice. Interestingly, the reduced footpad swelling in DKO mice is associated with a high footpad parasite level similar to susceptible IL-12p40-/- mice. In conclusion, this study demonstrate that in the absence of both STAT6 and IL-12p40 signaling, L. major -infected mice display smaller and less ulcerated lesions, which does, however, not correlate with reduced parasite load. In addition, the presence of neutrophils with an altered phenotype is associated with reduced apoptosis and delayed immunopathologies, demonstrating the detrimental role of STAT6 in infected susceptible BALB/c mice.- Published
- 2018
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14. CCR2-dependent monocyte-derived macrophages resolve inflammation and restore gut motility in postoperative ileus.
- Author
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Farro G, Stakenborg M, Gomez-Pinilla PJ, Labeeuw E, Goverse G, Di Giovangiulio M, Stakenborg N, Meroni E, D'Errico F, Elkrim Y, Laoui D, Lisowski ZM, Sauter KA, Hume DA, Van Ginderachter JA, Boeckxstaens GE, and Matteoli G
- Subjects
- Animals, Cell Differentiation, Cell Movement, Disease Models, Animal, Gastrointestinal Motility, Gastrointestinal Transit, Homeostasis immunology, Inflammation immunology, Inflammation pathology, Mice, Muscle, Smooth pathology, Ileus immunology, Ileus pathology, Macrophages immunology, Monocytes immunology, Postoperative Complications immunology, Postoperative Complications pathology, Receptors, CCR2 immunology
- Abstract
Objective: Postoperative ileus (POI) is assumed to result from myeloid cells infiltrating the intestinal muscularis externa (ME) in patients undergoing abdominal surgery. In the current study, we investigated the role of infiltrating monocytes in a murine model of intestinal manipulation (IM)-induced POI in order to clarify whether monocytes mediate tissue damage and intestinal dysfunction or they are rather involved in the recovery of gastrointestinal (GI) motility., Design: IM was performed in mice with defective monocyte migration to tissues (C-C motif chemokine receptor 2, Ccr2
-/ mice) and wild-type (WT) mice to study the role of monocytes and monocyte-derived macrophages (MΦs) during onset and resolution of ME inflammation., Results: At early time points, IM-induced GI transit delay and inflammation were equal in WT and Ccr2- - / - mice. However, GI transit recovery after IM was significantly delayed in Ccr2- / - mice compared with WT mice, associated with increased neutrophil-mediated immunopathology and persistent impaired neuromuscular function. During recovery, monocyte-derived MΦs acquire pro-resolving features that aided in the resolution of inflammation. In line, bone marrow reconstitution and treatment with MΦ colony-stimulating factor 1 enhanced monocyte recruitment and MΦ differentiation and ameliorated GI transit in Ccr2- / - mice., Conclusion: Our study reveals a critical role for monocyte-derived MΦs in restoring intestinal homeostasis after surgical trauma. From a therapeutic point of view, our data indicate that inappropriate targeting of monocytes may increase neutrophil-mediated immunopathology and prolong the clinical outcome of POI, while future therapies should be aimed at enhancing MΦ physiological repair functions., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)- Published
- 2017
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15. The tumour microenvironment harbours ontogenically distinct dendritic cell populations with opposing effects on tumour immunity.
- Author
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Laoui D, Keirsse J, Morias Y, Van Overmeire E, Geeraerts X, Elkrim Y, Kiss M, Bolli E, Lahmar Q, Sichien D, Serneels J, Scott CL, Boon L, De Baetselier P, Mazzone M, Guilliams M, and Van Ginderachter JA
- Subjects
- Animals, Cell Line, Tumor, Cells, Cultured, Humans, Immunotherapy methods, Macrophages immunology, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Monocytes immunology, Neoplasms pathology, Neoplasms therapy, T-Lymphocyte Subsets immunology, Dendritic Cells immunology, Neoplasms immunology, Tumor Microenvironment immunology
- Abstract
Various steady state and inflamed tissues have been shown to contain a heterogeneous DC population consisting of developmentally distinct subsets, including cDC1s, cDC2s and monocyte-derived DCs, displaying differential functional specializations. The identification of functionally distinct tumour-associated DC (TADC) subpopulations could prove essential for the understanding of basic TADC biology and for envisaging targeted immunotherapies. We demonstrate that multiple mouse tumours as well as human tumours harbour ontogenically discrete TADC subsets. Monocyte-derived TADCs are prominent in tumour antigen uptake, but lack strong T-cell stimulatory capacity due to NO-mediated immunosuppression. Pre-cDC-derived TADCs have lymph node migratory potential, whereby cDC1s efficiently activate CD8
+ T cells and cDC2s induce Th17 cells. Mice vaccinated with cDC2s displayed a reduced tumour growth accompanied by a reprogramming of pro-tumoural TAMs and a reduction of MDSCs, while cDC1 vaccination strongly induces anti-tumour CTLs. Our data might prove important for therapeutic interventions targeted at specific TADC subsets or their precursors.- Published
- 2016
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16. M-CSF and GM-CSF Receptor Signaling Differentially Regulate Monocyte Maturation and Macrophage Polarization in the Tumor Microenvironment.
- Author
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Van Overmeire E, Stijlemans B, Heymann F, Keirsse J, Morias Y, Elkrim Y, Brys L, Abels C, Lahmar Q, Ergen C, Vereecke L, Tacke F, De Baetselier P, Van Ginderachter JA, and Laoui D
- Subjects
- Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacology, Carcinoma, Lewis Lung drug therapy, Carcinoma, Lewis Lung immunology, Carcinoma, Lewis Lung metabolism, Carcinoma, Lewis Lung pathology, Cell Differentiation physiology, Cell Polarity physiology, Female, Macrophage Colony-Stimulating Factor immunology, Macrophage Colony-Stimulating Factor metabolism, Macrophages pathology, Mammary Neoplasms, Experimental drug therapy, Mammary Neoplasms, Experimental immunology, Mammary Neoplasms, Experimental metabolism, Mammary Neoplasms, Experimental pathology, Mice, Mice, Inbred C57BL, Monocytes pathology, Receptors, Colony-Stimulating Factor antagonists & inhibitors, Receptors, Colony-Stimulating Factor immunology, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor immunology, Signal Transduction, Macrophages metabolism, Monocytes metabolism, Receptors, Colony-Stimulating Factor metabolism, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Tumor Microenvironment physiology
- Abstract
Tumors contain a heterogeneous myeloid fraction comprised of discrete MHC-II(hi) and MHC-II(lo) tumor-associated macrophage (TAM) subpopulations that originate from Ly6C(hi) monocytes. However, the mechanisms regulating the abundance and phenotype of distinct TAM subsets remain unknown. Here, we investigated the role of macrophage colony-stimulating factor (M-CSF) in TAM differentiation and polarization in different mouse tumor models. We demonstrate that treatment of tumor-bearing mice with a blocking anti-M-CSFR monoclonal antibody resulted in a reduction of mature TAMs due to impaired recruitment, extravasation, proliferation, and maturation of their Ly6C(hi) monocytic precursors. M-CSFR signaling blockade shifted the MHC-II(lo)/MHC-II(hi) TAM balance in favor of the latter as observed by the preferential differentiation of Ly6C(hi) monocytes into MHC-II(hi) TAMs. In addition, the genetic and functional signatures of MHC-II(lo) TAMs were downregulated upon M-CSFR blockade, indicating that M-CSFR signaling shapes the MHC-II(lo) TAM phenotype. Conversely, granulocyte macrophage (GM)-CSFR had no effect on the mononuclear tumor infiltrate or relative abundance of TAM subsets. However, GM-CSFR signaling played an important role in fine-tuning the MHC-II(hi) phenotype. Overall, our data uncover the multifaceted and opposing roles of M-CSFR and GM-CSFR signaling in governing the phenotype of macrophage subsets in tumors, and provide new insight into the mechanism of action underlying M-CSFR blockade., (©2015 American Association for Cancer Research.)
- Published
- 2016
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17. Macrophage dynamics are regulated by local macrophage proliferation and monocyte recruitment in injured pancreas.
- Author
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Van Gassen N, Van Overmeire E, Leuckx G, Heremans Y, De Groef S, Cai Y, Elkrim Y, Gysemans C, Stijlemans B, Van de Casteele M, De Baetselier P, De Leu N, Heimberg H, and Van Ginderachter JA
- Subjects
- Animals, Antigens, Ly metabolism, Cell Movement immunology, Cell Proliferation, Cellular Microenvironment immunology, Histocompatibility Antigens Class II metabolism, Ligation, Macrophage Activation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myeloid Cells classification, Myeloid Cells immunology, Myeloid Cells pathology, Pancreas pathology, Pancreatic Ducts injuries, Receptor, Macrophage Colony-Stimulating Factor metabolism, Regeneration immunology, Macrophages immunology, Macrophages pathology, Monocytes immunology, Monocytes pathology, Pancreas immunology, Pancreas injuries
- Abstract
Pancreas injury by partial duct ligation (PDL) activates a healing response, encompassing β-cell neogenesis and proliferation. Macrophages (MΦs) were recently shown to promote β-cell proliferation after PDL, but they remain poorly characterized. We assessed myeloid cell diversity and the factors driving myeloid cell dynamics following acute pancreas injury by PDL. In naive and sham-operated pancreas, the myeloid cell compartment consisted mainly of two distinct tissue-resident MΦ types, designated MHC-II(lo) and MHC-II(hi) MΦs, the latter being predominant. MHC-II(lo) and MHC-II(hi) pancreas MΦs differed at the molecular level, with MHC-II(lo) MΦs being more M2-activated. After PDL, there was an early surge of Ly6C(hi) monocyte infiltration in the pancreas, followed by a transient MHC-II(lo) MΦ peak and ultimately a restoration of the MHC-II(hi) MΦ-dominated steady-state equilibrium. These intricate MΦ dynamics in PDL pancreas depended on monocyte recruitment by C-C chemokine receptor 2 and macrophage-colony stimulating factor receptor as well as on macrophage-colony stimulating factor receptor-dependent local MΦ proliferation. Functionally, MHC-II(lo) MΦs were more angiogenic. We further demonstrated that, at least in C-C chemokine receptor 2-KO mice, tissue MΦs, rather than Ly6C(hi) monocyte-derived MΦs, contributed to β-cell proliferation. Together, our study fully characterizes the MΦ subsets in the pancreas and clarifies the complex dynamics of MΦs after PDL injury., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2015
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18. Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population.
- Author
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Laoui D, Van Overmeire E, Di Conza G, Aldeni C, Keirsse J, Morias Y, Movahedi K, Houbracken I, Schouppe E, Elkrim Y, Karroum O, Jordan B, Carmeliet P, Gysemans C, De Baetselier P, Mazzone M, and Van Ginderachter JA
- Subjects
- Animals, Cell Differentiation physiology, Disease Models, Animal, Female, Macrophages pathology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neoplasms genetics, Transcriptome, Cell Hypoxia physiology, Macrophages metabolism, Neoplasms metabolism, Neoplasms pathology
- Abstract
Tumor-associated macrophages (TAM) are exposed to multiple microenvironmental cues in tumors, which collaborate to endow these cells with protumoral activities. Hypoxia, caused by an imbalance in oxygen supply and demand because of a poorly organized vasculature, is often a prominent feature in solid tumors. However, to what extent tumor hypoxia regulates the TAM phenotype in vivo is unknown. Here, we show that the myeloid infiltrate in mouse lung carcinoma tumors encompasses two morphologically distinct CD11b(hi)F4/80(hi)Ly6C(lo) TAM subsets, designated as MHC-II(lo) and MHC-II(hi) TAM, both of which were derived from tumor-infiltrating Ly6C(hi) monocytes. MHC-II(lo) TAM express higher levels of prototypical M2 markers and reside in more hypoxic regions. Consequently, MHC-II(lo) TAM contain higher mRNA levels for hypoxia-regulated genes than their MHC-II(hi) counterparts. To assess the in vivo role of hypoxia on these TAM features, cancer cells were inoculated in prolyl hydroxylase domain 2 (PHD2)-haplodeficient mice, resulting in better-oxygenated tumors. Interestingly, reduced tumor hypoxia did not alter the relative abundance of TAM subsets nor their M2 marker expression, but specifically lowered hypoxia-sensitive gene expression and angiogenic activity in the MHC-II(lo) TAM subset. The same observation in PHD2(+/+) → PHD2(+/-) bone marrow chimeras also suggests organization of a better-oxygenized microenvironment. Together, our results show that hypoxia is not a major driver of TAM subset differentiation, but rather specifically fine-tunes the phenotype of M2-like MHC-II(lo) TAM.
- Published
- 2014
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19. Adenosine 5'-monophosphate challenge elicits a more peripheral airway response than methacholine challenge.
- Author
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Michils A, Elkrim Y, Haccuria A, and Van Muylem A
- Subjects
- Adult, Female, Humans, Male, Respiratory Function Tests methods, Adenosine Monophosphate pharmacology, Asthma diagnosis, Asthma physiopathology, Lung drug effects, Lung physiopathology, Methacholine Chloride pharmacology, Pulmonary Ventilation drug effects
- Abstract
Adenosine 5'-monophosphate (AMP) and methacholine are commonly used to assess airway hyperreactivity. However, it is not fully known whether the site of airway constriction primarily involved during challenges with either agent is similar. Using a ventilation distribution test, we investigated whether the constriction induced by each agent involves the lung periphery in a similar fashion. Ventilation distribution was evaluated by the phase III slope (S) of the single-breath washout, using gases with different diffusivities like helium (He) and hexafluorosulfur (SF(6)). A greater postchallenge increase in S(He) reflects alterations at the level of terminal and respiratory bronchioles, while a greater increase in S(SF6) reflects alterations in alveolar ducts, increases to an equal extent reflecting alterations in more proximal airways where gas transport is still convective for both gases. S(SF6) and S(He) were measured in 15 asthma patients before and after airway challenges (20% forced expired volume in 1-s fall) with AMP and methacholine. S(He) increased to a greater extent than S(SF6) after AMP challenge (5.7 vs. 3.7%/l; P = 0.002), with both slopes increasing to an equal extent after methacholine challenge (3.1%/l; P = 0.959). The larger increase in S(He) following AMP challenge suggests distal ventilation impairment up to the level of terminal and respiratory bronchioles. With methacholine, the similar increases in S(He) and S(SF6) suggest a less distal impairment. AMP, therefore, seems to affect more extensively the very peripheral airways, whereas methacholine seems to have an effect on less distal airways.
- Published
- 2011
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