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1.
Gut ; 72(4): 699-709, 2023 04.
Article in English | MEDLINE | ID: mdl-35803702

ABSTRACT

OBJECTIVE: T cells are major effectors of the antitumoural immune response. Their activation by tumour-associated antigens can unleash their proliferation and cytotoxic functions, leading to tumour cell elimination. However, tumour-related immunosuppressive mechanisms including the overexpression of immune checkpoints like programmed cell death protein-1 (PD-1), are also engaged, promoting immune escape. Current immunotherapies targeting these pathways have demonstrated weak efficacy in colorectal cancer (CRC). It is thus crucial to find new targets for immunotherapy in this cancer type. DESIGN: In a prospective cohort of patients with CRC, we investigated the phenotype of tumour-related and non-tumour related intestinal T cells (n=44), particularly the adenosinergic pathway, correlating with clinical phenotype. An autologous coculture model was developed between patient-derived primary tumour spheroids and their autologous tumour-associated lymphocytes. We used this relevant model to assess the effects of CD39 blockade on the antitumour T cell response. RESULTS: We show the increased expression of CD39, and its co-expression with PD-1, on tumour infiltrating T cells compared with mucosal lymphocytes. CD39 expression was higher in the right colon and early-stage tumours, thus defining a subset of patients potentially responsive to CD39 blockade. Finally, we demonstrate in autologous conditions that CD39 blockade triggers T cell infiltration and tumour spheroid destruction in cocultures. CONCLUSION: In CRC, CD39 is strongly expressed on tumour infiltrating lymphocytes and its inhibition represents a promising therapeutic strategy for treating patients.


Subject(s)
Colorectal Neoplasms , T-Lymphocytes , Humans , Programmed Cell Death 1 Receptor/metabolism , Prospective Studies , Intestines/pathology , Colorectal Neoplasms/pathology
2.
J Clin Invest ; 131(13)2021 07 01.
Article in English | MEDLINE | ID: mdl-34043588

ABSTRACT

Peripheral T cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcomes. The T cell receptor (TCR) is emerging as a key driver of T lymphocyte transformation. However, the role of chronic TCR activation in lymphomagenesis and in lymphoma cell survival is still poorly understood. Using a mouse model, we report that chronic TCR stimulation drove T cell lymphomagenesis, whereas TCR signaling did not contribute to PTCL survival. The combination of kinome, transcriptome, and epigenome analyses of mouse PTCLs revealed a NK cell-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and SYK. Activating NKRs were functional in PTCLs and dependent on SYK activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKRs and downstream SYK/mTOR activity for their survival. We studied a large collection of human primary samples and identified several PTCLs recapitulating the phenotype described in this model by their expression of SYK and the NKR, suggesting a similar mechanism of lymphomagenesis and establishing a rationale for clinical studies targeting such molecules.


Subject(s)
Lymphoma, T-Cell, Peripheral/immunology , Receptors, Antigen, T-Cell/immunology , Receptors, Natural Killer Cell/immunology , Animals , Carcinogenesis/genetics , Carcinogenesis/immunology , Cellular Reprogramming/genetics , Cellular Reprogramming/immunology , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Genes, p53 , Humans , Killer Cells, Natural/immunology , Lymphoma, T-Cell, Peripheral/genetics , Lymphoma, T-Cell, Peripheral/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Neoplasms, Experimental/genetics , Neoplasms, Experimental/immunology , Neoplasms, Experimental/metabolism , Receptors, Antigen, T-Cell/genetics , Receptors, Natural Killer Cell/genetics , Signal Transduction/genetics , Signal Transduction/immunology , Syk Kinase/metabolism , T-Lymphocytes/immunology
3.
Open Res Eur ; 1: 107, 2021.
Article in English | MEDLINE | ID: mdl-35967081

ABSTRACT

Background: MICA and MICB are tightly regulated stress-induced proteins that trigger the immune system by binding to the activating receptor NKG2D on cytotoxic lymphocytes. MICA and MICB are highly polymorphic molecules with prevalent expression on several types of solid tumors and limited expression in normal/healthy tissues, making them attractive targets for therapeutic intervention. Methods: We have generated a series of anti-MICA and MICB cross-reactive antibodies with the unique feature of binding to the most prevalent isoforms of both these molecules. Results: The anti-MICA and MICB antibody MICAB1, a human IgG1 Fc-engineered monoclonal antibody (mAb), displayed potent antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of MICA/B-expressing tumor cells in vitro. However, it showed insufficient efficiency against solid tumors in vivo, which prompted the development of antibody-drug conjugates (ADC). Indeed, optimal tumor control was achieved with MICAB1-ADC format in several solid tumor models, including patient-derived xenografts (PDX) and carcinogen-induced tumors in immunocompetent MICAgen transgenic mice. Conclusions: These data indicate that MICA and MICB are promising targets for cytotoxic immunotherapy.

4.
Front Immunol ; 11: 960, 2020.
Article in English | MEDLINE | ID: mdl-32582150

ABSTRACT

NKG2D is a potent activating immunoreceptor expressed on nearly all cytotoxic lymphocytes promoting their cytotoxicity against self-cells expressing NKG2D ligands (NKG2DLs). NKG2DLs are MHC class I-like glycoproteins that usually are not expressed on "healthy" cells. Rather, their surface expression is induced by various forms of cellular stress, viral infection, or malignant transformation. Hence, cell surface NKG2DLs mark "dangerous" cells for elimination by cytotoxic lymphocytes and therefore can be considered as "kill-me" signals. In addition, NKG2DLs are up-regulated on activated leukocytes, which facilitates containment of immune responses. While the NKG2D receptor is conserved among mammals, NKG2DL genes have rapidly diversified during mammalian speciation, likely due to strong selective pressures exerted by species-specific pathogens. Consequently, NKG2DL genes are not conserved in man and mice, although their NKG2D-binding domains maintained structural homology. Human NKG2DLs comprise two members of the MIC (MICA/MICB) and six members of the ULBP family of glycoproteins (ULBP1-6) with MICA representing the best-studied human NKG2DLs by far. Many of these studies implicate a role of MICA in various malignant, infectious, or autoimmune diseases. However, conclusions from these studies often were limited in default of supporting in vivo experiments. Here, we report a MICA transgenic (MICAgen) mouse model that replicates central features of human MICA expression and function and, therefore, constitutes a novel tool to critically assess and extend conclusions from previous in vitro studies on MICA. Similarly to humans, MICA transcripts are broadly present in organs of MICAgen mice, while MICA glycoproteins are barely detectable. Upon activation, hematopoietic cells up-regulate and proteolytically shed surface MICA. Shed soluble MICA (sMICA) is also present in plasma of MICAgen mice but affects neither surface NKG2D expression of circulating NK cells nor their functional recognition of MICA-expressing tumor cells. Accordingly, MICAgen mice also show a delayed growth of MICA-expressing B16F10 tumors, not accompanied by an emergence of MICA-specific antibodies. Such immunotolerance for the xenoantigen MICA ideally suits MICAgen mice for anti-MICA-based immunotherapies. Altogether, MICAgen mice represent a valuable model to study regulation, function, disease relevance, and therapeutic targeting of MICA in vivo.


Subject(s)
Histocompatibility Antigens Class I/metabolism , Lymphocyte Activation , Lymphocytes/metabolism , Melanoma, Experimental/metabolism , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Animals , Cell Line, Tumor , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Immune Tolerance , Isoantibodies/immunology , Isoantibodies/metabolism , Ligands , Lymphocytes/immunology , Melanoma, Experimental/genetics , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Mice, Inbred C57BL , Mice, Transgenic , NK Cell Lectin-Like Receptor Subfamily K/deficiency , NK Cell Lectin-Like Receptor Subfamily K/genetics , Signal Transduction , Tumor Burden
5.
Semin Immunol ; 41: 101274, 2019 02.
Article in English | MEDLINE | ID: mdl-31072659

ABSTRACT

Immunotherapies have revolutionized cancer treatment over the last 20 years. They aim either to boost immune cell activation or decrease immune cell inhibition, to improve control over cancer development. Various strategies for improving tumor immunity have been tested. Some have been approved and others are currently in clinical trials. They target the immune system itself, the tumor cells or the microenvironment. Most focus on enhancing T-cell responses, notably through infusions of activating cytokines, the adoptive transfer of activated or engineered T cells, or immune checkpoint inhibitors. ILCs have also emerged as an interesting target for immunotherapy, initially due to the anti-tumor activities of cytotoxic NK cells. However, the other helper-like ILCs can also infiltrate the tumor microenvironment, having either pro- or anti-tumor effects, depending on their phenotype and the type of cancer. Moreover, given the similarities between helper ILCs and T cells in terms of their cytokine profiles and the surface markers they express, immunotherapies targeting T cells may also target helper-like ILCs. We provide here an overview of the field, summarizing the evidence for a role of helper-like ILCs and ways of targeting these cells in solid tumors and hematological malignancies.


Subject(s)
Immunity, Innate , Immunotherapy , Neoplasms/immunology , Neoplasms/therapy , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Animals , Cell Plasticity/immunology , Humans , Immunotherapy/methods , Tumor Microenvironment/immunology
6.
J Immunother Cancer ; 7(1): 74, 2019 03 14.
Article in English | MEDLINE | ID: mdl-30871626

ABSTRACT

BACKGROUND: Immunotherapies still fail to benefit colorectal cancer (CRC) patients. Relevant functional assays aimed at studying these failures and the efficacy of cancer immunotherapy in human are scarce. 3D tumor cultures, called tumor organoids or spheroids, represent interesting models to study cancer treatments and could help to challenge these issues. METHODS: We analyzed heterotypic cocultures of human colon tumor-derived spheroids with immune cells to assess the infiltration, activation and function of T and NK cells toward human colorectal tumors in vitro. RESULTS: We showed that allogeneic T and NK cells rapidly infiltrated cell line-derived spheroids, inducing immune-mediated tumor cell apoptosis and spheroid destruction. NKG2D, a key activator of cytotoxic responses, was engaged on infiltrating cells. We thus assessed the therapeutic potential of an antibody targeting the specific ligands of NKG2D, MICA and MICB, in this system. Anti-MICA/B enhanced immune-dependent destruction of tumor spheroid by driving an increased NK cells infiltration and activation. Interestingly, tumor cells reacted to immune infiltration by upregulating HLA-E, ligand of the inhibitory receptor NKG2A expressed by CD8 and NK cells. NKG2A was increased after anti-MICA/B treatment and, accordingly, combination of anti-MICA/B and anti-NKG2A was synergistic. These observations were ultimately confirmed in a clinical relevant model of coculture between CRC patients-derived spheroids and autologous tumor-infiltrating lymphocytes. CONCLUSIONS: Altogether, we show that tumor spheroids represent a relevant tool to study tumor-lymphocyte interactions on human tissues and revealed the antitumor potential of immunomodulatory antibodies targeting MICA/B and NKG2A.


Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Colorectal Neoplasms/immunology , Histocompatibility Antigens Class I/metabolism , NK Cell Lectin-Like Receptor Subfamily C/metabolism , Spheroids, Cellular/cytology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Coculture Techniques , Colorectal Neoplasms/drug therapy , HT29 Cells , Humans , Killer Cells, Natural/immunology , Molecular Targeted Therapy , Spheroids, Cellular/drug effects , Spheroids, Cellular/metabolism , T-Lymphocytes/immunology
7.
Cell ; 175(7): 1731-1743.e13, 2018 12 13.
Article in English | MEDLINE | ID: mdl-30503213

ABSTRACT

Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8+ T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8+ T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Squamous Cell , Cetuximab/therapeutic use , Immunity, Cellular/drug effects , Immunotherapy , Killer Cells, Natural/immunology , NK Cell Lectin-Like Receptor Subfamily C , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/therapy , Clinical Trials, Phase II as Topic , Humans , Killer Cells, Natural/pathology , Mice , NK Cell Lectin-Like Receptor Subfamily C/antagonists & inhibitors , NK Cell Lectin-Like Receptor Subfamily C/immunology
9.
Elife ; 62017 09 06.
Article in English | MEDLINE | ID: mdl-28875936

ABSTRACT

NK cell education is the process through which chronic engagement of inhibitory NK cell receptors by self MHC-I molecules preserves cellular responsiveness. The molecular mechanisms responsible for NK cell education remain unclear. Here, we show that mouse NK cell education is associated with a higher basal activity of the mTOR/Akt pathway, commensurate to the number of educating receptors. This higher activity was dependent on the SHP-1 phosphatase and essential for the improved responsiveness of reactive NK cells. Upon stimulation, the mTOR/Akt pathway amplified signaling through activating NK cell receptors by enhancing calcium flux and LFA-1 integrin activation. Pharmacological inhibition of mTOR resulted in a proportional decrease in NK cell reactivity. Reciprocally, acute cytokine stimulation restored reactivity of hyporesponsive NK cells through mTOR activation. These results demonstrate that mTOR acts as a molecular rheostat of NK cell reactivity controlled by educating receptors and uncover how cytokine stimulation overcomes NK cell education.


Subject(s)
Killer Cells, Natural/immunology , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Animals , Calcium/metabolism , Cells, Cultured , Cytokines/metabolism , Lymphocyte Function-Associated Antigen-1/metabolism , Mice, Inbred C57BL , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Proto-Oncogene Proteins c-akt/metabolism
10.
Haematologica ; 101(5): 626-33, 2016 05.
Article in English | MEDLINE | ID: mdl-26721894

ABSTRACT

Natural killer cells are key cells of the innate immune system. Natural killer cell receptor repertoires are diversified by a stochastic expression of killer-cell-immunoglobulin-like receptors and lectin-like receptors such as NKG2 receptors. All individuals harbor a subset of natural killer cells expressing NKG2A, the inhibitory checkpoint receptor for HLA-E. Most neoplastic and normal hematopoietic cells express HLA-E, the inhibitory ligand of NKG2A. A novel anti-human NKG2A antibody induced tumor cell death, suggesting that the antibody could be useful in the treatment of cancers expressing HLA-E. We found that immunodeficient mice, co-infused with human primary leukemia or Epstein-Barr virus cell lines and NKG2A(+) natural killer cells, pre-treated with anti-human NKG2A, were rescued from disease progression. Human NKG2A(+) natural killer cells reconstituted in immunodeficient mice after transplantation of human CD34(+) cells. These natural killer cells are able to kill engrafted human primary leukemia or Epstein-Barr virus cell lines by lysis after intraperitoneal administration of anti-human NKG2A. Thus, this anti-NKG2A may exploit the anti-leukemic action of the wave of NKG2A(+) natural killer cells recovering after hematopoietic stem cell transplants or adoptive therapy with natural killer cell infusions from matched or mismatched family donors after chemotherapy for acute leukemia, without the need to search for a natural killer cell alloreactive donor.


Subject(s)
Antibodies, Monoclonal/pharmacology , Bone Marrow Cells/drug effects , NK Cell Lectin-Like Receptor Subfamily C/antagonists & inhibitors , Animals , Bone Marrow Cells/immunology , Bone Marrow Cells/metabolism , Cell Line, Transformed , Cytotoxicity, Immunologic , Disease Models, Animal , Female , Histocompatibility Antigens Class I/immunology , Humans , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Leukemia/drug therapy , Leukemia/metabolism , Leukemia/mortality , Leukemia/pathology , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Lymphocyte Depletion/methods , Mice , HLA-E Antigens
11.
Cancer Res ; 74(21): 6060-70, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-25361998

ABSTRACT

Advanced cutaneous T-cell lymphoma (CTCL) remains an unmet medical need, which lacks effective targeted therapies. In this study, we report the development of IPH4102, a humanized monoclonal antibody that targets the immune receptor KIR3DL2, which is widely expressed on CTCL cells but few normal immune cells. Potent antitumor properties of IPH4102 were documented in allogeneic human CTCL cells and a mouse model of KIR3DL2(+) disease. IPH4102 antitumor activity was mediated by antibody-dependent cell cytotoxicity and phagocytosis. IPH4102 improved survival and reduced tumor growth in mice inoculated with KIR3DL2(+) tumors. Ex vivo efficacy was further evaluated in primary Sézary patient cells, sorted natural killer-based autologous assays, and direct spiking into Sézary patient peripheral blood mononuclear cells. In these settings, IPH4102 selectively and efficiently killed primary Sézary cells, including at unfavorable effector-to-target ratios characteristic of unsorted PBMC. Together, our results offer preclinical proof of concept for the clinical development of IPH4102 to treat patients with advanced CTCL.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/immunology , Receptors, KIR3DL2/immunology , Animals , Antibody-Dependent Cell Cytotoxicity/immunology , Cell Line, Tumor , Humans , Lymphoma, T-Cell, Cutaneous/pathology , Mice , Neoplasm Staging , Receptors, KIR3DL2/biosynthesis
12.
MAbs ; 6(3): 577-618, 2014.
Article in English | MEDLINE | ID: mdl-24589717

ABSTRACT

The 24th Antibody Engineering & Therapeutics meeting brought together a broad range of participants who were updated on the latest advances in antibody research and development. Organized by IBC Life Sciences, the gathering is the annual meeting of The Antibody Society, which serves as the scientific sponsor. Preconference workshops on 3D modeling and delineation of clonal lineages were featured, and the conference included sessions on a wide variety of topics relevant to researchers, including systems biology; antibody deep sequencing and repertoires; the effects of antibody gene variation and usage on antibody response; directed evolution; knowledge-based design; antibodies in a complex environment; polyreactive antibodies and polyspecificity; the interface between antibody therapy and cellular immunity in cancer; antibodies in cardiometabolic medicine; antibody pharmacokinetics, distribution and off-target toxicity; optimizing antibody formats for immunotherapy; polyclonals, oligoclonals and bispecifics; antibody discovery platforms; and antibody-drug conjugates.


Subject(s)
Antibodies/chemistry , Antibodies/therapeutic use , Animals , Antibodies/genetics , Directed Molecular Evolution , Drug Design , Humans , Immunotherapy , Neoplasms/therapy , Protein Engineering , Societies, Scientific , Systems Biology
13.
Blood ; 123(5): 678-86, 2014 Jan 30.
Article in English | MEDLINE | ID: mdl-24326534

ABSTRACT

Natural killer (NK) cells mediate antilymphoma activity by spontaneous cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) when triggered by rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. The balance of inhibitory and activating signals determines the magnitude of the efficacy of NK cells by spontaneous cytotoxicity. Here, using a killer-cell immunoglobulin-like receptor (KIR) transgenic murine model, we show that blockade of the interface of inhibitory KIRs with major histocompatibility complex (MHC) class I antigens on lymphoma cells by anti-KIR antibodies prevents a tolerogenic interaction and augments NK-cell spontaneous cytotoxicity. In combination with anti-CD20 mAbs, anti-KIR treatment induces enhanced NK-cell-mediated, rituximab-dependent cytotoxicity against lymphoma in vitro and in vivo in KIR transgenic and syngeneic murine lymphoma models. These results support a therapeutic strategy of combination rituximab and KIR blockade through lirilumab, illustrating the potential efficacy of combining a tumor-targeting therapy with an NK-cell agonist, thus stimulating the postrituximab antilymphoma immune response.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antigens, CD20/immunology , Killer Cells, Natural/immunology , Lymphoma/therapy , Receptors, KIR/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal, Murine-Derived/immunology , Antibody-Dependent Cell Cytotoxicity , Cell Line , Female , Histocompatibility Antigens Class I/immunology , Humans , Lymphoma/immunology , Male , Mice , Rituximab
14.
J Immunol ; 190(11): 5355-62, 2013 Jun 01.
Article in English | MEDLINE | ID: mdl-23687193

ABSTRACT

NK cells are important players in immunity against pathogens and neoplasms. As a component of the innate immune system, they are one of the first effectors on sites of inflammation. Through their cytokine production capacities, NK cells participate in the development of a potent adaptive immune response. Furthermore, NK cells were found to have regulatory functions to limit and prevent autoimmunity via killing of autologous immune cells. These paradoxical functions of NK cells are reflected in CNS disorders. In this review, we discuss the phenotypes and functional features of peripheral and brain NK cells in brain tumors and infections, neurodegenerative diseases, acute vascular and traumatic damage, as well as mental disorders. We also discuss the implication of NK cells in neurotoxicity and neuroprotection following CNS pathology, as well as the crosstalk between NK cells and brain-resident immune cells.


Subject(s)
Central Nervous System Diseases/immunology , Killer Cells, Natural/immunology , Animals , Brain/immunology , Brain/metabolism , Brain/pathology , Central Nervous System Diseases/metabolism , Humans , Killer Cells, Natural/metabolism , Phenotype
15.
Blood ; 118(24): 6387-91, 2011 Dec 08.
Article in English | MEDLINE | ID: mdl-22031859

ABSTRACT

Multiple myeloma (MM) patients who receive killer cell Ig-like receptor (KIR) ligand-mismatched, T cell-depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients who receive KIR ligand-matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Killer Cells, Natural/drug effects , Multiple Myeloma/drug therapy , Receptors, KIR/antagonists & inhibitors , Thalidomide/analogs & derivatives , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antigen-Antibody Complex , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Cells, Cultured , Cytotoxicity, Immunologic/drug effects , Drug Evaluation, Preclinical , Humans , Immunomodulation/drug effects , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lenalidomide , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Ligands , Mice , Mice, Inbred C57BL , Multiple Myeloma/blood , Multiple Myeloma/immunology , Multiple Myeloma/metabolism , Thalidomide/pharmacology , Thalidomide/therapeutic use , Up-Regulation/drug effects , Xenograft Model Antitumor Assays
16.
J Biomed Biotechnol ; 2011: 986491, 2011.
Article in English | MEDLINE | ID: mdl-21629707

ABSTRACT

Severe sepsis and septic shock are still deadly conditions urging to develop novel therapies. A better understanding of the complex modifications of the immune system of septic patients is needed for the development of innovative immunointerventions. Natural killer (NK) cells are characterized as CD3(-)NKp46(+)CD56(+) cells that can be cytotoxic and/or produce high amounts of cytokines such as IFN-γ. NK cells are also engaged in crosstalks with other immune cells, such as dendritic cells, macrophages, and neutrophils. During the early stage of septic shock, NK cells may play a key role in the promotion of the systemic inflammation, as suggested in mice models. Alternatively, at a later stage, NK cells-acquired dysfunction could favor nosocomial infections and mortality. Standardized biological tools defining patients' NK cell status during the different stages of sepsis are mandatory to guide potential immuno-interventions. Herein, we review the potential role of NK cells during severe sepsis and septic shock.


Subject(s)
Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Models, Immunological , Sepsis/immunology , Sepsis/pathology , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/pathology , Animals , Humans , Mice
17.
J Immunol ; 185(4): 2080-8, 2010 Aug 15.
Article in English | MEDLINE | ID: mdl-20639488

ABSTRACT

Cross-talk between NK cells and dendritic cells (DCs) is critical for the potent therapeutic response to dsRNA, but the receptors involved remained controversial. We show in this paper that two dsRNAs, polyadenylic-polyuridylic acid and polyinosinic-polycytidylic acid [poly(I:C)], similarly engaged human TLR3, whereas only poly(I:C) triggered human RIG-I and MDA5. Both dsRNA enhanced NK cell activation within PBMCs but only poly(I:C) induced IFN-gamma. Although myeloid DCs (mDCs) were required for NK cell activation, induction of cytolytic potential and IFN-gamma production did not require contact with mDCs but was dependent on type I IFN and IL-12, respectively. Poly(I:C) but not polyadenylic-polyuridylic acid synergized with mDC-derived IL-12 for IFN-gamma production by acting directly on NK cells. Finally, the requirement of both TLR3 and Rig-like receptor (RLR) on mDCs and RLRs but not TLR3 on NK cells for IFN-gamma production was demonstrated using TLR3- and Cardif-deficient mice and human RIG-I-specific activator. Thus, we report the requirement of cotriggering TLR3 and RLR on mDCs and RLRs on NK cells for a pathogen product to induce potent innate cell activation.


Subject(s)
DEAD-box RNA Helicases/metabolism , Dendritic Cells/drug effects , Interferon-gamma/metabolism , Killer Cells, Natural/drug effects , Toll-Like Receptor 3/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Line , Cells, Cultured , DEAD Box Protein 58 , DEAD-box RNA Helicases/genetics , Dendritic Cells/cytology , Dendritic Cells/metabolism , Dose-Response Relationship, Drug , Humans , Interferon-Induced Helicase, IFIH1 , Killer Cells, Natural/cytology , Killer Cells, Natural/metabolism , Lymphocyte Activation/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Cells/cytology , Myeloid Cells/drug effects , Myeloid Cells/metabolism , Poly A-U/pharmacology , Poly I-C/pharmacology , RNA, Double-Stranded/pharmacology , Receptors, Immunologic , Toll-Like Receptor 3/genetics , Transfection
18.
Proc Natl Acad Sci U S A ; 106(31): 12879-84, 2009 Aug 04.
Article in English | MEDLINE | ID: mdl-19561305

ABSTRACT

Natural killer (NK) cells are lymphocytes of the innate immune system able to recognize and kill tumors lacking self-MHC class I molecules. This "missing-self" recognition is mediated by the lack of engagement of MHC class I-specific inhibitory NK cell receptors that include the killer cell Ig-like receptors (KIR) in humans and Ly49 molecules in mice. A promising immunotherapeutic strategy against MHC class I(+) cancer cells is to block NK cell inhibitory receptors using monoclonal antibodies (mAb). However, interactions between MHC class I molecules and their inhibitory receptors are also required for the acquisition of NK cell functional competence, a process referred as to "education." In addition, inhibitory receptors are involved in self-tolerance on educated NK cells. Here, we developed a preclinical mouse model in which all NK cells are educated by a single transgenic inhibitory receptor, human KIR2DL3, through the engagement with its HLA-Cw3 ligand. This approach revealed that NK cells could be reprogrammed to control the development of mouse syngenic tumors in vivo. Moreover, in vivo anti-KIR mAb treatment induced the killing of HLA(+) target cells without breaking self-tolerance. Finally, the long-term infusion of anti-KIR mAb neither abolished NK cell education nor tumor cell recognition. Therefore, these results strongly support the use of inhibitory receptor blockade in cancer patients.


Subject(s)
Antibodies, Monoclonal/therapeutic use , HLA-C Antigens/physiology , Killer Cells, Natural/immunology , Neoplasms, Experimental/therapy , Receptors, KIR2DL3/physiology , Self Tolerance , Animals , Cell Line , Humans , Immunity, Innate , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/immunology , Receptors, KIR2DL3/immunology
19.
Proc Natl Acad Sci U S A ; 104(9): 3384-9, 2007 Feb 27.
Article in English | MEDLINE | ID: mdl-17360655

ABSTRACT

Natural killer (NK) cells contribute to a variety of innate immune responses to viruses, tumors and allogeneic cells. However, our understanding of NK cell biology is severely limited by the lack of consensus phenotypic definition of these cells across species, by the lack of specific marker to visualize them in situ, and by the lack of a genetic model where NK cells may be selectively ablated. NKp46/CD335 is an Ig-like superfamily cell surface receptor involved in human NK cell activation. In addition to human, we show here that NKp46 is expressed by NK cells in all mouse strains analyzed, as well as in three common monkey species, prompting a unifying phenotypic definition of NK cells across species based on NKp46 cell surface expression. Mouse NKp46 triggers NK cell effector function and allows the detection of NK cells in situ. NKp46 expression parallels cell engagement into NK differentiation programs because it is detected on all NK cells from the immature CD122(+)NK1.1(+)DX5(-) stage and on a minute fraction of NK-like T cells, but not on CD1d-restricted NKT cells. Moreover, human NKp46 promoter drives NK cell selective expression both in vitro and in vivo. Using NKp46 promoter, we generated transgenic mice expressing EGFP and the diphtheria toxin (DT) receptor in NK cells. DT injection in these mice leads to a complete and selective NK cell ablation. This model paves a way for the in vivo characterization and preclinical assessment of NK cell biological function.


Subject(s)
Gene Expression Regulation/immunology , Killer Cells, Natural/cytology , Membrane Glycoproteins/metabolism , Receptors, Immunologic/metabolism , Animals , Antigens, Ly , Cell Differentiation/immunology , Diphtheria Toxin/toxicity , Flow Cytometry , Green Fluorescent Proteins/metabolism , Haplorhini , Immunophenotyping , Killer Cells, Natural/drug effects , Killer Cells, Natural/metabolism , Membrane Glycoproteins/genetics , Mice , Mice, Transgenic , Microscopy, Fluorescence , Natural Cytotoxicity Triggering Receptor 1 , Promoter Regions, Genetic/genetics , Receptors, Immunologic/genetics
20.
J Exp Med ; 203(7): 1773-83, 2006 Jul 10.
Article in English | MEDLINE | ID: mdl-16801401

ABSTRACT

Divergent hypotheses exist to explain how signaling by the B cell receptor (BCR) is initiated after antigen binding and how it is qualitatively altered in anergic B cells to selectively uncouple from nuclear factor kappaB and c-Jun N-terminal kinase pathways while continuing to activate extracellular signal-regulated kinase and calcium-nuclear factor of activated T cell pathways. Here we find that BCRs on anergic cells are endocytosed at a very enhanced rate upon binding antigen, resulting in a large steady-state pool of intracellularly sequestered receptors that appear to be continuously cycling between surface and intracellular compartments. This endocytic mechanism is exquisitely sensitive to the lowering of plasma membrane cholesterol by methyl-beta-cyclodextrin, and, when blocked in this way, the sequestered BCRs return to the cell surface and RelA nuclear accumulation is stimulated. In contrast, when plasma membrane cholesterol is lowered and GM1 sphingolipid markers of membrane rafts are depleted in naive B cells, this does not diminish BCR signaling to calcium or RelA. These results provide a possible explanation for the signaling changes in clonal anergy and indicate that a chief function of membrane cholesterol in B cells is not to initiate BCR signaling, but instead to terminate a subset of signals by rapid receptor internalization.


Subject(s)
B-Lymphocytes/immunology , Cholesterol/physiology , Clonal Anergy/immunology , Membrane Lipids/physiology , NF-kappa B/metabolism , Receptors, Antigen, B-Cell/metabolism , Animals , B-Lymphocytes/metabolism , Clonal Anergy/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Antigen, B-Cell/genetics , Signal Transduction/genetics
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