23 results on '"Benlalam H"'
Search Results
2. Therapeutic efficiency of the infusion of TIL specific for melanoma antigens: O20
- Author
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Labarriére, N., Dréno, B., Benlalam, H., Pandolfino, M C, Khammari, A., and Jotereau, F.
- Published
- 2004
3. Immune surveillance of human cancer: if the cytotoxic T‐lymphocytes play the music, does the tumoral system call the tune?
- Author
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Hamaï, A., primary, Benlalam, H., additional, Meslin, F., additional, Hasmim, M., additional, Carré, T., additional, Akalay, I., additional, Janji, B., additional, Berchem, G., additional, Noman, M. Z., additional, and Chouaib, S., additional
- Published
- 2009
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4. Targeting NKG2A to boost anti-tumor CD8 T-cell responses in human colorectal cancer.
- Author
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Ducoin K, Oger R, Bilonda Mutala L, Deleine C, Jouand N, Desfrançois J, Podevin J, Duchalais E, Cruard J, Benlalam H, Labarrière N, Bossard C, Jarry A, and Gervois-Segain N
- Subjects
- Humans, Killer Cells, Natural immunology, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating pathology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Colorectal Neoplasms drug therapy, Colorectal Neoplasms immunology, Colorectal Neoplasms pathology, NK Cell Lectin-Like Receptor Subfamily C immunology
- Abstract
Recently, the inhibitory CD94/NKG2A receptor has joined the group of immune checkpoints (ICs) and its expression has been documented in NK cells and CD8
+ T lymphocytes in several cancers and some infectious diseases. In colorectal cancer (CRC), we previously reported that NKG2A+ tumor-infiltrating lymphocytes (TILs) are predominantly CD8+ αβ T cells and that CD94 overexpression and/or its ligand HLA-E were associated with a poor prognosis. This study aimed to thoroughly characterize the NKG2A+ CD8+ TIL subpopulation and document the impact of NKG2A on anti-tumor responses in CRC. Our findings highlight new features of this subpopulation: (i) enrichment in colorectal tumors compared to paired normal colonic mucosa, (ii) their character as tissue-resident T cells and their majority terminal exhaustion status, (iii) co-expression of other ICs delineating two subgroups differing mainly in the level of NKG2A expression and the presence of PD-1, (iv) high functional avidity despite reduced proliferative capacity and finally (v) inhibition of anti-tumor reactivity that is overcome by blocking NKG2A. From a clinical point of view, these results open a promising alternative for immunotherapies based on NKG2A blockade in CRC, which could be performed alone or in combination with other IC inhibitors, adoptive cell transfer or therapeutic vaccination., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)- Published
- 2022
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5. Engineering a Human Plasmacytoid Dendritic Cell-Based Vaccine to Prime and Expand Multispecific Viral and Tumor Antigen-Specific T-Cells.
- Author
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Lenogue K, Walencik A, Laulagnier K, Molens JP, Benlalam H, Dreno B, Coulie P, Pule M, Chaperot L, and Plumas J
- Abstract
Because dendritic cells are crucial to prime and expand antigen-specific CD8
+ T-cells, several strategies are designed to use them in therapeutic vaccines against infectious diseases or cancer. In this context, off-the-shelf allogeneic dendritic cell-based platforms are more attractive than individualized autologous vaccines tailored to each patient. In the present study, a unique dendritic cell line (PDC*line) platform of plasmacytoid origin, already used to prime and expand antitumor immunity in melanoma patients, was improved thanks to retroviral engineering. We demonstrated that the clinical-grade PDC*line, transduced with genes encoding viral or tumoral whole proteins, efficiently processed and stably presented the transduced antigens in different human leukocyte antigen (HLA) class I contexts. Moreover, the use of polyepitope constructs allowed the presentation of immunogenic peptides and the expansion of specific cytotoxic effectors. We also demonstrated that the addition of the Lysosome-associated membrane protein-1 (LAMP-1) sequence greatly improved the presentation of some peptides. Lastly, thanks to transduction of new HLA molecules, the PDC platform can benefit many patients through the easy addition of matched HLA-I molecules. The demonstration of the effective retroviral transduction of PDC*line cells strengthens and broadens the scope of the PDC*line platform, which can be used in adoptive or active immunotherapy for the treatment of infectious diseases or cancer.- Published
- 2021
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6. Viral and tumor antigen-specific CD8 T-cell responses in Merkel cell carcinoma.
- Author
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Samimi M, Benlalam H, Aumond P, Gaboriaud P, Fradin D, Kervarrec T, Florenceau L, Vignard V, Blom A, Touzé A, Gervois N, and Labarriere N
- Subjects
- Animals, Antigens, Neoplasm immunology, Antigens, Viral immunology, COS Cells, Cell Line, Tumor, Chlorocebus aethiops, Epitopes, T-Lymphocyte immunology, Female, HLA Antigens immunology, Humans, Male, Neoplasm Proteins immunology, CD8-Positive T-Lymphocytes immunology, Carcinoma, Merkel Cell immunology, Skin Neoplasms immunology
- Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer, which is immunogenic, regardless of the presence of MCPyV (80% of cases). The identification of MCC-specific epitopes recognized by CD8 T cells is crucial to expand the arsenal of immunotherapeutic treatments. Until now, most efforts focused on the identification of virus-specific epitopes, whereas immune responses directed against shared cellular tumor-specific antigens have not been evidenced. In this study, we measured T-cell responses against viral (n = 3) and tumor antigens (n = 47) from TILs derived from 21 MCC tumors. Virus-specific CD8 T-cell responses dominated MCC-specific immune responses, and we identified two new HLA-peptide complexes derived from the LT antigen, located in a region encompassing 3 previously identified epitopes. Finally, we show that MAGE-A3 antigen, frequently expressed by MCC tumors, was recognized by CD8 TILs from a virus-negative MCC tumor and thus could be a target for immunotherapy in this setting., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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7. Merkel cell carcinoma and cellular cytotoxicity: sensitivity to cellular lysis and screening for potential target antigens suitable for antibody-dependent cellular cytotoxicity.
- Author
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Ollier J, Kervarrec T, Samimi M, Benlalam H, Aumont P, Vivien R, Touzé A, Labarrière N, Vié H, and Clémenceau B
- Subjects
- Carcinoma, Merkel Cell metabolism, Carcinoma, Merkel Cell pathology, Cells, Cultured, Histocompatibility Antigens Class I metabolism, Humans, Interferon-gamma metabolism, Skin Neoplasms metabolism, Skin Neoplasms pathology, Tumor Cells, Cultured, Antibodies, Monoclonal immunology, Antibody-Dependent Cell Cytotoxicity immunology, Antigens, Neoplasm immunology, Carcinoma, Merkel Cell immunology, Killer Cells, Natural immunology, Skin Neoplasms immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
The recent success of checkpoint inhibitors in the treatment of Merkel cell carcinoma (MCC) confirms that MCC tumors can be immunogenic. However, no treatment directly targeting the tumor is available for use in combination with these checkpoint inhibitors to enhance their efficacity. This study was carried out to characterize MCC line sensitivity to cellular lysis and to identify cell surface antigens that could be used for direct targeting of this tumor. For five representative MCC lines, the absence or low expression of MICA, MICB, HLA-I, and ICAM-1 was associated with low level of recognition by NK cells and T lymphocytes. However, expression of HLA-I and ICAM-1 and sensitivity to cellular lysis could be restored or increased after exposure to INFγ. We tested 41 antibodies specific for 41 different antigens using a novel antibody-dependent cellular cytotoxicity (ADCC) screening system for target antigens. Anti-CD326 (EpCAM) was the only antibody capable of inducing ADCC on the five MCC lines tested. Because MCC tumors are often directly accessible, local pharmacologic manipulation to restore HLA class-I and ICAM-1 cell surface expression (and thus sensitivity to cell lysis) can potentially benefit immune therapeutic intervention. In line with this, our observation that ADCC against EpCAM can induce lysis of MCC lines and suggests that therapeutic targeting of this antigen deserves to be explored further.
- Published
- 2018
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8. Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAF V600E Melanoma Lines with Vemurafenib.
- Author
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Frazao A, Colombo M, Fourmentraux-Neves E, Messaoudene M, Rusakiewicz S, Zitvogel L, Vivier E, Vély F, Faure F, Dréno B, Benlalam H, Bouquet F, Savina A, Pasmant E, Toubert A, Avril MF, and Caignard A
- Subjects
- B7 Antigens immunology, Cell Lineage immunology, Cell Proliferation drug effects, GPI-Linked Proteins immunology, Gene Expression Regulation, Neoplastic drug effects, Gene Expression Regulation, Neoplastic immunology, Histocompatibility Antigens Class I immunology, Humans, Indoles immunology, Intercellular Signaling Peptides and Proteins immunology, Melanoma genetics, Melanoma immunology, Melanoma pathology, Mutation, NK Cell Lectin-Like Receptor Subfamily K immunology, Natural Cytotoxicity Triggering Receptor 3 immunology, Natural Killer T-Cells drug effects, Proto-Oncogene Proteins B-raf immunology, Sulfonamides immunology, Vemurafenib, Indoles administration & dosage, Melanoma drug therapy, Natural Killer T-Cells immunology, Proto-Oncogene Proteins B-raf genetics, Sulfonamides administration & dosage
- Abstract
Over 60% of human melanoma tumors bear a mutation in the BRAF gene. The most frequent mutation is a substitution at codon 600 (V600E), leading to a constitutively active BRAF and overactivation of the MAPK pathway. Patients harboring mutated BRAF respond to kinase inhibitors such as vemurafenib. However, these responses are transient, and relapses are frequent. Melanoma cells are efficiently lysed by activated natural killer (NK) cells. Melanoma cells express several stress-induced ligands that are recognized by activating NK-cell receptors. We have investigated the effect of vemurafenib on the immunogenicity of seven BRAF -mutated melanoma cells to NK cells and on their growth and sensitivity to NK-cell-mediated lysis. We showed that vemurafenib treatment modulated expression of ligands for two activating NK receptors, increasing expression of B7-H6, a ligand for NKp30, and decreasing expression of MICA and ULBP2, ligands for NKG2D. Vemurafenib also increased expression of HLA class I and HLA-E molecules, likely leading to higher engagement of inhibitory receptors (KIRs and NKG2A, respectively), and decreased lysis of vemurafenib-treated melanoma cell lines by cytokine-activated NK cells. Finally, we showed that whereas batimastat (a broad-spectrum matrix metalloprotease inhibitor) increased cell surface ULBP2 by reducing its shedding, vemurafenib lowered soluble ULBP2, indicating that BRAF signal inhibition diminished expression of both cell-surface and soluble forms of NKG2D ligands. Vemurafenib, inhibiting BRAF signaling, shifted the balance of activatory and inhibitory NK ligands on melanoma cells and displayed immunoregulatory effects on NK-cell functional activities. Cancer Immunol Res; 5(7); 582-93. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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9. CD40L confers helper functions to human intra-melanoma class-I-restricted CD4 + CD8 + double positive T cells.
- Author
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Parrot T, Oger R, Benlalam H, Raingeard de la Blétière D, Jouand N, Coutolleau A, Preisser L, Khammari A, Dréno B, Guardiola P, Delneste Y, Labarrière N, and Gervois N
- Abstract
Although CD4
+ CD8+ double positive (DP) T cells represent a small fraction of peripheral T lymphocytes in healthy human donors, their frequency is often increased under pathological conditions (in blood and targeted tissues). In solid cancers such as melanoma, we previously demonstrated an enrichment of tumor reactive CD4low CD8high αβ DP T cells among tumor-infiltrating lymphocytes of unknown function. Similarly to their single positive (SP) CD8+ counterparts, intra-melanoma DP T cells recognized melanoma cell lines in an HLA-class-I restricted context. However, they presented a poor cytotoxic activity but a strong production of diverse Th1 and Th2 cytokines. The aim of this study was to clearly define the role of intra-melanoma CD4low CD8high αβ DP T cells in the antitumor immune response. Based on a comparative transcriptome analysis between intra-melanoma SP CD4+ , SP CD8+ and DP autologous melanoma-infiltrating T-cell compartments, we evidenced an overexpression of the CD40L co-stimulatory molecule on activated DP T cells. We showed that, like SP CD4+ T cells, and through CD40L involvement, DP T cells are able to induce both proliferation and differentiation of B lymphocytes and maturation of functional DCs able to efficiently prime cytotoxic melanoma-specific CD8 T-cell responses. Taken together, these results highlight the helper potential of atypical DP T cells and their role in potentiating antitumor response.- Published
- 2016
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10. IL-9 promotes the survival and function of human melanoma-infiltrating CD4(+) CD8(+) double-positive T cells.
- Author
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Parrot T, Allard M, Oger R, Benlalam H, Raingeard de la Blétière D, Coutolleau A, Preisser L, Desfrançois J, Khammari A, Dréno B, Labarrière N, Delneste Y, Guardiola P, and Gervois N
- Subjects
- Apoptosis drug effects, Apoptosis immunology, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cell Survival immunology, Cells, Cultured, Cytokines metabolism, Cytotoxicity, Immunologic drug effects, Gene Expression, Humans, Interleukin-9 pharmacology, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Lymphocytes, Tumor-Infiltrating drug effects, Melanoma genetics, Melanoma pathology, Receptors, Interleukin-9 genetics, Receptors, Interleukin-9 metabolism, T-Lymphocyte Subsets drug effects, Interleukin-9 immunology, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Melanoma immunology, Melanoma metabolism, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism
- Abstract
We previously demonstrated an accumulation of tumor-reactive CD4(+) CD8(+) double positive (DP) T cells within melanoma-infiltrating lymphocytes, supporting their role in the regulation of anti-tumor immune responses. Similarly to their CD8(+) counterparts, intra-tumor DP T cells are MHC class-I restricted but differed by a limited lytic activity against autologous melanoma cells. Based on these observations and to further characterize DP T cells, both populations were compared at the transcriptional level. Our results revealed the overexpression of the IL-9 receptor (IL-9R) by DP T cells and prompted us to investigate the impact of IL-9 on their biology. We show that IL-9 favors DP T-cell survival by protecting them from apoptosis and by promoting their proliferation. In addition, IL-9 enhances their ability to produce cytokines and increased their levels of granzyme B/perforin as well as degranulation capacity, leading to a strengthened cytotoxic activity against melanoma cells. Taken together, the IL-9R(high) DP T-cell population could be a new preferential target for IL-9, which could take part in their retention within the melanoma infiltrate while also favoring their anti-tumor activity. More generally, our results extend the pleiotropic effects of IL-9 to IL-9R-expressing intra-tumor T cells, which could further potentiate anti-tumor immune responses., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
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11. Soluble HLA-I/peptide monomers mediate antigen-specific CD8 T cell activation through passive peptide exchange with cell-bound HLA-I molecules.
- Author
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Allard M, Oger R, Benlalam H, Florenceau L, Echasserieau K, Bernardeau K, Labarrière N, Lang F, and Gervois N
- Subjects
- CD8-Positive T-Lymphocytes cytology, Female, HeLa Cells, Humans, Male, Protein Transport immunology, Solubility, CD8-Positive T-Lymphocytes immunology, Histocompatibility Antigens Class I immunology, Peptides immunology
- Abstract
Accumulating evidence that serum levels of soluble class I HLA molecules (sHLA-I) can, under various pathological conditions, correlate with disease stage and/or patient survival, has stimulated interest in defining whether sHLA-I can exert immunological functions. However, despite a mounting number of publications suggesting the ability of sHLA-I to affect immune effectors in vitro, the precise underlying mechanism still remains controversial. In this article, we address potential functions of both classical and nonclassical sHLA-I, using soluble recombinant HLA-I/peptide monomers, and clearly demonstrate their ability to trigger Ag-specific activation of CD8 T cells in vitro. Furthermore, we provide strong evidence that this behavior results from the passive transfer of peptides from monomers to T cell-bound HLA-I molecules, allowing for fratricide representation and activation. Hence, we proposed a unifying model of T cell activation by HLA-I/peptide monomers, reappraising the potential involvement of sHLA-I molecules in the immune response., (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Published
- 2014
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12. Regulation of gap junctions in melanoma and their impact on Melan-A/MART-1-specific CD8⁺ T lymphocyte emergence.
- Author
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Benlalam H, Carré T, Jalil A, Noman Z, Caillou B, Vielh P, Tittarelli A, Robert C, and Chouaib S
- Subjects
- Antineoplastic Agents, Alkylating pharmacology, Apoptosis genetics, Apoptosis immunology, Cell Line, Tumor, Connexin 43 genetics, Connexin 43 metabolism, Cytotoxicity, Immunologic genetics, Dacarbazine pharmacology, Gap Junctions drug effects, Gap Junctions metabolism, Gene Expression, Humans, Hypoxia, Immunological Synapses metabolism, Interferon-gamma pharmacology, Melanoma genetics, Melanoma metabolism, Oxidative Stress, Protein Transport, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic metabolism, CD8-Positive T-Lymphocytes immunology, Gap Junctions immunology, MART-1 Antigen immunology, Melanoma immunology
- Abstract
Unlabelled: Gap junctions (GJs) enable intercellular communication between adjacent cells through channels of connexins. Using a three-dimensional construct, we previously showed that endothelial and tumor cells formed GJs, allowing melanoma-specific T lymphocytes to recognize and kill melanoma-derived endothelial cells. We demonstrate here on histological sections of melanoma biopsies that GJ formation occurs in vivo between tumor and endothelial cells and between T lymphocytes and target cells. We also show an in vitro increase of GJ formation in melanoma and endothelial cells following dacarbazin and interferon gamma (IFN-γ) treatment or hypoxic stress induction. Our data indicate that although connexin 43 (Cx43), the main GJ protein of the immune system, was localized at the immunological synapse between T lymphocyte and autologous melanoma cells, its over-expression or inhibition of GJs does not interfere with cytotoxic T lymphocyte (CTL) clone lytic function. In contrast, we showed that inhibition of GJs by oleamide during stimulation of resting PBMCs with Melan-A natural and analog peptides resulted in a decrease in antigen (Ag) specific CD8(+) T lymphocyte induction. These Ag-specific CD8(+) cells displayed paradoxically stronger reactivity as revealed by CD107a degranulation and IFN-γ secretion. These findings indicate that Cx43 does not affect lytic function of differentiated CTL, but reveal a major role for GJs in the regulation of antigen CD8(+)-naïve T lymphocyte activation., Key Message: GJ formation occurs in vivo between T lymphocytes and tumor cells Cx43 localized at the immunological synapse between T and autologous melanoma cells Inhibition of GJs resulted in a decrease in Ag-specific CD8(+) T lymphocyte induction A role for GJs in the regulation of antigen CD8(+)-naïve T lymphocyte activation.
- Published
- 2013
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13. Hypoxia-dependent inhibition of tumor cell susceptibility to CTL-mediated lysis involves NANOG induction in target cells.
- Author
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Hasmim M, Noman MZ, Lauriol J, Benlalam H, Mallavialle A, Rosselli F, Mami-Chouaib F, Alcaide-Loridan C, and Chouaib S
- Subjects
- Blotting, Western, Cell Hypoxia genetics, Cell Line, Tumor, Cell Separation, Flow Cytometry, Gene Expression, Gene Expression Regulation immunology, Homeodomain Proteins genetics, Homeodomain Proteins immunology, Humans, Microscopy, Confocal, Nanog Homeobox Protein, Neoplasms metabolism, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Cytotoxic metabolism, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Cell Hypoxia immunology, Homeodomain Proteins biosynthesis, Neoplasms immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Hypoxia is a major feature of the solid tumor microenvironment and is known to be associated with tumor progression and poor clinical outcome. Recently, we reported that hypoxia protects human non-small cell lung tumor cells from specific lysis by stabilizing hypoxia-inducible factor-1α and inducing STAT3 phosphorylation. In this study, we show that NANOG, a transcription factor associated with stem cell self renewal, is a new mediator of hypoxia-induced resistance to specific lysis. Our data indicate that under hypoxic conditions, NANOG is induced at both transcriptional and translational levels. Knockdown of the NANOG gene in hypoxic tumor cells is able to significantly attenuate hypoxia-induced tumor resistance to CTL-dependent killing. Such knockdown correlates with an increase of target cell death and an inhibition of hypoxia-induced delay of DNA replication in these cells. Interestingly, NANOG depletion results in inhibition of STAT3 phosphorylation and nuclear translocation. To our knowledge, this study is the first to show that hypoxia-induced NANOG plays a critical role in tumor cell response to hypoxia and promotes tumor cell resistance to Ag-specific lysis.
- Published
- 2011
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14. Cytotoxic T cells - stroma interactions.
- Author
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Noman MZ, Benlalam H, Hasmim M, and Chouaib S
- Subjects
- Antigen Presentation physiology, Cell Communication immunology, Cell Hypoxia immunology, Disease Progression, Endothelial Cells immunology, Killer Cells, Natural immunology, Killer Cells, Natural physiology, Melanoma immunology, STAT3 Transcription Factor physiology, T-Lymphocytes, Cytotoxic immunology, Tumor Microenvironment immunology, Vascular Endothelial Growth Factor A physiology, Cell Communication physiology, Cell Hypoxia physiology, Endothelial Cells physiology, Hypoxia-Inducible Factor 1, alpha Subunit physiology, Neoplasm Proteins physiology, T-Lymphocytes, Cytotoxic physiology, Tumor Microenvironment physiology
- Abstract
The tumor microenvironment is a complex system playing an important role in tumor development and progression. Besides tumor cells, the tumor microenvironment harbours a variety of host-derived cells, such as endothelial cells, fibroblasts, innate and adaptive immune cells, as well as extracellular matrix (ECM) fibers, cytokines, and other mediators. This review discusses the potential role of hypoxia and endothelial cells within tumor microenvironment and emphasizes their interaction with antigen specific killer cells.
- Published
- 2011
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15. The anti-angiogenic activity of IL-12 is increased in iNOS-/- mice and involves NK cells.
- Author
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Bielawska-Pohl A, Blesson S, Benlalam H, Trenado A, Opolon P, Bawa O, Rouffiac V, Dus D, Kieda C, and Chouaib S
- Subjects
- Animals, Endothelial Cells pathology, Gene Knockout Techniques, Killer Cells, Natural pathology, Melanoma, Experimental blood supply, Melanoma, Experimental pathology, Mice, Mice, Inbred C57BL, Neovascularization, Pathologic pathology, Nitric Oxide immunology, Vascular Endothelial Growth Factor A immunology, Interleukin-12 immunology, Killer Cells, Natural immunology, Melanoma, Experimental immunology, Neovascularization, Pathologic immunology, Nitric Oxide Synthase Type II genetics
- Abstract
We have previously reported that the in vivo transfer of murine interleukin-12 (IL-12) gene using a Semliki Forest virus vector induced tumor regression through inhibition of tumor blood vessel formation. To examine whether IL-12 anti-angiogenic activity interferes with the NO pathway, we used inducible nitric oxide synthase-deficient mice (iNOS-/-) and demonstrated that the anti-tumor effect of IL-12 is more pronounced in these mice. In addition, despite the increased level of intratumoral VEGF in iNOS-/- mice, IL-12 induced a stronger inhibition of blood vessel formation. Histological analysis of SFV-IL-12-treated tumors showed an increase in natural killer (NK) perivascular infiltration in iNOS-/- as compared to control mice. In vitro IL-12-stimulated murine splenic NK cells displayed significant killing activity towards established murine endothelial cells used as targets. These studies indicate that the anti-angiogenic activity of IL-12 interferes with iNOS pathway and involves NK cell recruitment.
- Published
- 2010
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16. Endothelial cells as key determinants of the tumor microenvironment: interaction with tumor cells, extracellular matrix and immune killer cells.
- Author
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Chouaib S, Kieda C, Benlalam H, Noman MZ, Mami-Chouaib F, and Rüegg C
- Subjects
- Animals, Humans, Neoplasms blood supply, Cell Communication, Endothelial Cells immunology, Extracellular Matrix immunology, Killer Cells, Natural immunology, Neoplasms immunology, Tumor Microenvironment
- Abstract
Besides tumor cells, the tumor microenvironment harbors a variety of host-derived cells, such as endothelial cells, fibroblasts, innate and adaptive immune cells. It is a complex and highly dynamic environment, providing very important cues to tumor development and progression. Tumor-associated endothelial cells play a key role in this process. On the one hand, they form tumor-associated (angiogenic) vessels through sprouting from locally preexisting vessels or recruitment of bone marrow-derived endothelial progenitor cells, to provide nutritional support to the growing tumor. On the other hand, they are the interface between circulating blood cells, tumor cells and the extracellular matrix, thereby playing a central role in controlling leukocyte recruitment, tumor cell behavior and metastasis formation. Hypoxia is a critical parameter modulating the tumor microenvironment and endothelial/tumor cell interactions. Under hypoxic stress, tumor cells produce factors that promote tumor angiogenesis, tumor cell motility and metastasis. Among these factors, VEGF, a main angiogenesis modulator, can also play a critical role in the control of immune tolerance. This review discusses some aspects of the role of endothelial cells within tumor microenvironment and emphasizes their interaction with tumor cells, the extracellular matrix and with immune killer cells. We will also address the role played by circulating endothelial progenitor cells and illustrate their features and mechanism of recruitment to the tumor microenvironment and their role in tumor angiogenesis.
- Published
- 2010
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17. Gap junction communication between autologous endothelial and tumor cells induce cross-recognition and elimination by specific CTL.
- Author
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Benlalam H, Jalil A, Hasmim M, Pang B, Tamouza R, Mitterrand M, Godet Y, Lamerant N, Robert C, Avril MF, Neefjes J, Tursz T, Mami-Chouaib F, Kieda C, and Chouaib S
- Subjects
- Antigens, Neoplasm metabolism, Biomarkers metabolism, Biomarkers, Tumor metabolism, Cell Line, Tumor, Clone Cells, Coculture Techniques, Cytosol immunology, Cytosol metabolism, Cytotoxicity, Immunologic immunology, Endothelial Cells metabolism, Gap Junctions metabolism, Gap Junctions pathology, Humans, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Lymphocytes, Tumor-Infiltrating pathology, Melanoma therapy, T-Lymphocytes, Cytotoxic metabolism, T-Lymphocytes, Cytotoxic pathology, Cell Communication immunology, Cross-Priming immunology, Endothelial Cells immunology, Endothelial Cells pathology, Gap Junctions immunology, Melanoma immunology, Melanoma pathology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Cellular interactions in the tumor stroma play a major role in cancer progression but can also induce tumor rejection. To explore the role of endothelial cells in these interactions, we used an in vitro three-dimensional collagen matrix model containing a cytotoxic T lymphocyte CTL clone (M4.48), autologous tumor cells (M4T), and an endothelial cell (M4E) line that are all derived from the same tumor. We demonstrate in this study that specific killing of the endothelial cells by the CTL clone required the autologous tumor cells and involved Ag cross-presentation. The formation of gap junctions between endothelial and tumor cells is required for antigenic peptide transfer to endothelial cells that are then recognized and eliminated by CTL. Our results indicate that gap junctions facilitate an effective CTL-mediated destruction of endothelial cells from the tumor microenvironment that may contribute to the control of tumor progression.
- Published
- 2009
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18. ICAM-1 has a critical role in the regulation of metastatic melanoma tumor susceptibility to CTL lysis by interfering with PI3K/AKT pathway.
- Author
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Hamaï A, Meslin F, Benlalam H, Jalil A, Mehrpour M, Faure F, Lecluse Y, Vielh P, Avril MF, Robert C, and Chouaib S
- Subjects
- Antigen Presentation, Antigens, Neoplasm immunology, Cell Line, Tumor, Down-Regulation, Enzyme Activation, G1 Phase immunology, Humans, Intercellular Adhesion Molecule-1 biosynthesis, Intercellular Adhesion Molecule-1 genetics, Interferon-gamma pharmacology, MART-1 Antigen, Melanoma enzymology, Melanoma secondary, Neoplasm Proteins immunology, PTEN Phosphohydrolase metabolism, RNA, Small Interfering genetics, Serpins biosynthesis, Serpins immunology, Intercellular Adhesion Molecule-1 immunology, Melanoma immunology, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, T-Lymphocytes, Cytotoxic immunology
- Abstract
Human primary melanoma cells (T1) were found to be more susceptible to lysis by a Melan-A/MART-1-specific CTL clone (LT12) than their metastatic derivative (G1). We show that this differential susceptibility does not involve antigen presentation by target cells, synapse formation between the metastatic target and CTL clone, or subsequent granzyme B (GrB) polarization. Although PI-9, an inhibitor of GrB, was found to be overexpressed in metastatic G1 cells, knockdown of the PI-9 gene did not result in the attenuation of G1 resistance to CTL-induced killing. Interestingly, we show that whereas T1 cells express high levels of intercellular adhesion molecule-1 (ICAM-1), a dramatically reduced expression was noted on G1 cells. We also showed that sorted ICAM-1+ G1 cells were highly sensitive to CTL-induced lysis compared with ICAM-1- G1 cells. Furthermore, incubation of metastatic G1 cells with IFN-gamma resulted in the induction of ICAM-1 and the potentiation of their susceptibility to lysis by LT12. More importantly, we found that the level of ICAM-1 expression by melanoma cells correlated with decreased PTEN activity. ICAM-1 knockdown in T1 cells resulted in increased phosphorylation of PTEN and the subsequent activation of AKT. We have additionally shown that inhibition of the phosphatidylinositol (3,4,5)-triphosphate kinase (PI3K)/AKT pathway by the specific inhibitor wortmannin induced a significant potentiation of susceptibility of G1 and ICAM-1 small interfering RNA-treated T1 cells to CTL-induced lysis. The present study shows that a shift in ICAM-1 expression, which was associated with an activation of the PI3K/AKT pathway, can be used by metastatic melanoma cells to escape CTL-mediated killing.
- Published
- 2008
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19. Infusion of Melan-A/Mart-1 specific tumor-infiltrating lymphocytes enhanced relapse-free survival of melanoma patients.
- Author
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Benlalam H, Vignard V, Khammari A, Bonnin A, Godet Y, Pandolfino MC, Jotereau F, Dreno B, and Labarrière N
- Subjects
- Animals, COS Cells, Chlorocebus aethiops, Disease-Free Survival, HLA-A2 Antigen, Humans, Lymphocytes, Tumor-Infiltrating immunology, MART-1 Antigen, Melanoma mortality, Survival Analysis, T-Lymphocytes immunology, Transplantation, Autologous, Antigens, Neoplasm immunology, Immunotherapy, Adoptive, Lymphocytes, Tumor-Infiltrating transplantation, Melanoma therapy, Neoplasm Proteins immunology, T-Lymphocytes transplantation
- Abstract
Adoptive therapy of cancer has been mostly tested in advanced cancer patients using tumor-infiltrating lymphocytes (TIL). Following discouraging results likely due to poor tumor-specificity of TIL and/or high tumor burden, recent studies reiterate the enormous potential of this therapy, particularly in melanoma. We had performed a phase II/III randomised trial on 88 stage III melanoma patients, who received autologous TIL plus IL-2 or IL-2 alone, after complete tumour resection. We reported previously clinical and immunological results supporting the ability of tumor reactive TIL infusion to prevent further development of the melanoma disease and to increase overall survival of patients bearing only one tumor invaded lymph node. The absence of correlation between overall and disease-free survival and the amount of infused tumor-specific TIL suggested that therapeutic efficiency might depend on other parameters such as antigen specificity, function or persistence of TIL. Here we studied the recognition of a panel of 38 shared tumor-associated antigens (TAA) by TIL infused to the patients included in this assay, in order to determine if treatment outcome could correlate with particular antigen specificities of infused TIL. Results show that the infusion of Melan-A/MART-1 reactive TIL appears to be associated with a longer relapse-free survival for HLA-A2 patients. These results further support the relevance of Melan-A/MART-1 antigen as a prime target for immunotherapy protocols in melanoma.
- Published
- 2007
- Full Text
- View/download PDF
20. [Immunotherapy of cancer: promise and reality].
- Author
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Chouaib S, El Hage F, Benlalam H, and Mami-Chouaib F
- Subjects
- Antigens, Neoplasm immunology, Cancer Vaccines therapeutic use, Cytotoxicity, Immunologic, Dendritic Cells immunology, Humans, Immunization, Passive, Neoplasms therapy, Immunotherapy trends, Neoplasms immunology
- Abstract
The notion that the immune system regulates cancer development is now well established. An overwhelming amount of data from animal models, together with compelling data from human patients, indicate that the immune system is instrumental in scanning and irradicating tumors. Analysis of individuals with congenital or acquired immunodeficiencies or patients undergoing immunosuppressive therapy has documented a highly elevated incidence of virally induced malignancies and cancers compared with immunocompetent individuals [1-3]. During the last decade, thanks to the breakthoughts in understanding the molecular mechanisms responsible for immune activation, the tumor antigen identification, the dendritic cell biology, the immunogenecity of tumors, the immune escape mechanisms, the host-tumor relationship, we are facing a new area of tumor immunotherapy. The basic advances were translated in therapeutical applications and have changed the view of immunotherapy from "a dream scenario" to a clinical fourth modality to cancer treatments. Multiple cancer trials using active immunization with vaccines or adoptive immunotherapy have been conducted with only very limited success. There are still a number of issues that still need to be resolved including a better understanding of immune escape mechanisms. Cancer vaccines continue to be evaluated and may lead to the emergence of clinically useful new treatments. A comprehensive approach to define the intricate molecular program initiated by tumor cells to resist to escape and the immune system of the host may help in breaking down the barriers to a more adapted cancer immunotherapy.
- Published
- 2006
- Full Text
- View/download PDF
21. Identification of five new HLA-B*3501-restricted epitopes derived from common melanoma-associated antigens, spontaneously recognized by tumor-infiltrating lymphocytes.
- Author
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Benlalam H, Linard B, Guilloux Y, Moreau-Aubry A, Derré L, Diez E, Dreno B, Jotereau F, and Labarrière N
- Subjects
- Animals, Antigens, Neoplasm chemistry, Antigens, Neoplasm immunology, COS Cells, Cell Division immunology, Cell Line, Transformed, Cell Line, Tumor, Clone Cells, Cytotoxicity Tests, Immunologic, Epitopes, T-Lymphocyte immunology, Epitopes, T-Lymphocyte metabolism, HLA-B35 Antigen immunology, HLA-B35 Antigen isolation & purification, Humans, MART-1 Antigen, Melanoma enzymology, Melanoma pathology, Membrane Glycoproteins immunology, Membrane Glycoproteins metabolism, Mice, Monophenol Monooxygenase immunology, Monophenol Monooxygenase metabolism, Neoplasm Proteins immunology, Neoplasm Proteins metabolism, Peptide Fragments chemistry, Peptide Fragments immunology, Peptide Fragments metabolism, Protein Binding immunology, Proteins immunology, Proteins metabolism, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic pathology, gp100 Melanoma Antigen, Antigen Presentation, Antigens, Neoplasm metabolism, Epitopes, T-Lymphocyte isolation & purification, HLA-B35 Antigen metabolism, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating metabolism, Melanoma immunology, Membrane Proteins
- Abstract
We previously described HLA-B35-restricted melanoma tumor-infiltrating lymphocyte responses to frequently expressed melanoma-associated Ags: tyrosinase, Melan-A/MART-1, gp100, MAGE-A3/MAGE-A6, and NY-ESO-1. Using clones derived from these TIL, we identified in this study the corresponding epitopes. We show that five of these epitopes are new and that melanoma cells naturally present all the six epitopes. Interestingly, five of these epitopes correspond to or encompass melanoma-associated Ag epitopes presented in other HLA contexts, such as A2, A1, B51, and Cw3. In particular, the HLA-B35-restricted Melan-A epitope is mimicked by the peptide 26-35, already known as the most immunodominant melanoma epitope in the HLA-A*0201 context. Because this peptide lacked adequate anchor amino acid residues for efficient binding to HLA-B35, modified peptides were designed. Two of these analogues were found to induce higher PBL- and tumor-infiltrating lymphocyte-specific responses than the parental peptide, suggesting that they could be more immunogenic in HLA-B*3501 melanoma patients. These data have important implications for the formulation of polypeptide-based vaccines as well as for the monitoring of melanoma-specific CTL response in HLA-B*3501 melanoma patients.
- Published
- 2003
- Full Text
- View/download PDF
22. A ras-mutated peptide targeted by CTL infiltrating a human melanoma lesion.
- Author
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Linard B, Bézieau S, Benlalam H, Labarrière N, Guilloux Y, Diez E, and Jotereau F
- Subjects
- Animals, Antigens, Neoplasm genetics, COS Cells, Cells, Cultured, Clone Cells, Epitopes, T-Lymphocyte immunology, HLA-A Antigens metabolism, Humans, Melanoma genetics, Melanoma pathology, Oncogene Protein p21(ras) genetics, Peptides immunology, Point Mutation, Tumor Cells, Cultured, Antigens, Neoplasm immunology, Lymphocytes, Tumor-Infiltrating immunology, Melanoma immunology, Oncogene Protein p21(ras) immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Ags derived from commonly mutated oncogenic proteins seem ideally suited as targets for tumor immunotherapy. Nonetheless, only a few mutated epitopes efficiently presented by human tumors have thus far been identified. We describe here an approach to identify such epitopes. This approach involves: 1) identifying tumors expressing a ras mutation and isolating the tumor-infiltrating lymphocytes (TIL); 2) transfecting COS cells to induce expression of unknown mutated peptides in the context of a patient's HLA class I molecules; and 3) screening epitope recognition by using TIL from the tumors expressing a ras mutation. By using this approach, there appeared to be a N-ras mutation (a glutamine-to-arginine exchange at residue 61 (Q61R)), detected in a melanoma lesion, which was recognized specifically by the autologous TIL in the HLA-A*0101 context. The ras peptide 55-64(Q61R) was the epitope of these TIL and was regularly presented by Q61R-mutated HLA-A*0101(+) melanoma cell lines. This peptide and its wild-type homolog (55-64(wt)) bound to HLA-A*0101 with similar affinities. However, only the mutated peptide could induce specific CTL expansion from PBL. All the CTL clones specific to the mutated peptide, failed to recognize the wild-type sequence on both COS and melanoma cells. These data thus show that oncogenic protein mutations can create shared tumor-specific CTL epitopes, efficiently presented by tumor cells, and that screening for oncogene-transfected COS cell recognition by TIL (from tumors containing mutations) is a powerful approach for the identification of these epitopes.
- Published
- 2002
- Full Text
- View/download PDF
23. Comprehensive analysis of the frequency of recognition of melanoma-associated antigen (MAA) by CD8 melanoma infiltrating lymphocytes (TIL): implications for immunotherapy.
- Author
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Benlalam H, Labarrière N, Linard B, Derré L, Diez E, Pandolfino MC, Bonneville M, and Jotereau F
- Subjects
- Animals, Antigen Presentation, Antigens, Neoplasm immunology, COS Cells, Cancer Vaccines, Cell Differentiation, Clone Cells, Epitopes immunology, HLA Antigens immunology, Humans, Melanoma therapy, Melanoma-Specific Antigens, Mice, Neoplasm Proteins genetics, Transfection, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha biosynthesis, Lymphocytes, Tumor-Infiltrating immunology, Melanoma immunology, Neoplasm Proteins immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Fifty-nine tumor-infiltrating lymphocyte (TIL) cultures established from melanoma-invaded lymph nodes were screened for recognition of 28 melanoma-associated antigens (MAA) in association with31 HLA molecules. Twenty-three (39%) TIL lines reacted to at least one melanoma antigen. Melanosomal proteins were recognized by 19 TIL populations and the most prominent responses against these proteins were directed against Melan-A/MART-1 (mainly in association with HLA-A*0201) and gp100 (in association with diverse HLA contexts). Ten TIL populations reacted against 10 tumor-specific antigens, in association with 8 different HLA molecules. HLA-A*0201 and B*3501-restricted responses were the most frequent with, respectively, 17 and 7 responses directed against 5 distinct antigens. Unexpectedly, the recognition by TIL of different MAA was frequently restricted by a single HLA in individual tumors, and there was no evidence for the existence of dominant MAA epitopes between tumors,except for Melan-A/MART-1 antigen. This analysis also led to the detection of 21 new HLA-peptide complexes recognized by melanoma TIL. This study, which is to our knowledge the most comprehensive analysis of TIL specificity to tumor antigens, has several implications for the design of immunotherapeutic strategies based on immunization against selected tumor epitopes.
- Published
- 2001
- Full Text
- View/download PDF
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