Faculte Of Medecine Of Luniversite Paris Sud Xi

Le Kremlin-Bicêtre, France

Faculte Of Medecine Of Luniversite Paris Sud Xi

Le Kremlin-Bicêtre, France
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Andrews D.M.,Peter MacCallum Cancer Center | Chow M.T.,Peter MacCallum Cancer Center | Ma Y.,Institute Gustave Roussy | Ma Y.,French Institute of Health and Medical Research | And 11 more authors.
Immunology and Cell Biology | Year: 2011

Toll-like receptor-4-lipopolysaccharide (LPS)-mediated inflammation is used to delineate signals involved in cross-talk between antigen-presenting cells (APCs) and lymphocytes such as natural killer (NK) cells. Following APC stimulation and cytokine release, NK cells produce interferon (IFN)-γ. High levels of LPS induce endotoxicosis, a systemic inflammatory disease in which IFN-γ causes significant morbidity and mortality. Several studies have highlighted the role of interleukin (IL)-18, IL-1Β, IL-17A and IFN-γ in the development of endotoxicosis, but whether these cytokines interact with each other is yet to be determined. Our data demonstrate that IL-18 and IL-17A have important roles in NK cell IFN-γ production during endotoxicosis. Importantly, we provide the first evidence that IL-18 also has a role in IL-17A production by T-cell receptor (TCR)-cells. Furthermore, we demonstrate that IL-18-deficient mice have a defect in γ T-cell homeostasis and IL-1Β production, both of which can contribute to the development of disease through induction of IL-17A. These results reveal novel requirements for IL-18 in innate immune cell homeostasis and activation, demonstrating that the role of IL-18 in innate immunity occurs at a level other than activation. © 2011 Australasian Society for Immunology Inc. All rights reserved.

Zoubir M.,French Institute of Health and Medical Research | Zoubir M.,CNRS Gustave Roussy Institute | Zoubir M.,Faculte Of Medecine Of Luniversite Paris Sud Xi | Flament C.,French Institute of Health and Medical Research | And 27 more authors.
Cell Cycle | Year: 2011

Cyclin-dependent kinase (CDK) inhibitors have been considered as excellent drug candidates for cancer therapy owing to their potential capacity to restore cell cycle control. The first generation of CDK inhibitors showed modest clinical advantages that could be attributed to off-target effects preventing them from reaching therapeutic concentrations. A phase I dose-escalation study using the second generation multi-CDK inhibitor PHA-793887 was conducted on a total of 19 patients with advanced refractory malignancies in two sites in Europe: the University of Leeds and St. James's Institute of Oncology, Leeds, UK, and the Institut Gustave Roussy, Villeujf, France (IGR). Fifteen patients were treated at IGR. Six among these patients manifested the reactivation of herpes virus replication. In vitro experiments revealed that PHA-793887 severely impaired signaling by toll-like receptors (such as TLR3, TLR4 and TLR9) in dendritic cells (DC), thus suppressing the production of multiple cytokines (type 1 interferon, interleukin-6, -10, -12 and tumor necrosis factorα) by mature DC, as well as the DC-stimulated production of interferonγ by natural killer cells. Pharmacological inhibition of glycogen synthase-3β (GSK-3β), one of the off-targets of PHA-793887, did not cause such immunological defects. Altogether, these data underscore a hitherto unsuspected immunosuppressive effect of PHA-793887. © 2011 Landes Bioscience.

Viaud S.,French Institute of Health and Medical Research | Viaud S.,Institute Gustave Roussy | Thery C.,Institute Curie | Thery C.,French Institute of Health and Medical Research | And 16 more authors.
Cancer Research | Year: 2010

Exosomes are nanovesicles originating from late endosomal compartments and secreted by most living cells in ex vivo cell culture conditions. The interest in exosomes was rekindled when B-cell and dendritic cell-derived exosomes were shown to mediate MHC-dependent immune responses. Despite limited understanding of exosome biogenesis and physiological relevance, accumulating evidence points to their bioactivity culminating in clinical applications in cancer. This review focuses on the preclinical studies exploiting the immunogenicity of dendritic cell-derived exosomes (Dex) and will elaborate on the past and future vaccination trials conducted using Dex strategy in melanoma and non-small cell lung cancer patients. ©2010 AACR.

Ma Y.,French Institute of Health and Medical Research | Ma Y.,Ecole Doctorale Of Cancerologie Of Luniversite Paris Sud Xi | Aymeric L.,French Institute of Health and Medical Research | Aymeric L.,Ecole Doctorale Of Cancerologie Of Luniversite Paris Sud Xi | And 30 more authors.
Journal of Experimental Medicine | Year: 2011

By triggering immunogenic cell death, some anticancer compounds, including anthracyclines and oxaliplatin, elicit tumor-specific, interferon-γ- producing CD8+ αβ T lymphocytes (Tc1 CTLs) that are pivotal for an optimal therapeutic outcome. Here, we demonstrate that chemotherapy induces a rapid and prominent invasion of interleukin (IL)-17-producing γδ (Vγ4+ and Vγ6 +) T lymphocytes (γδ T17 cells) that precedes the accumulation of Tc1 CTLs within the tumor bed. In T cell receptor δ-/- or Vγ4/6-/- mice, the therapeutic efficacy of chemotherapy was compromised, no IL-17 was produced by tumor-infiltrating T cells, and Tc1 CTLs failed to invade the tumor after treatment. Although γδ T17 cells could produce both IL-17A and IL-22, the absence of a functional IL-17A-IL-17R pathway significantly reduced tumor-specific T cell responses elicited by tumor cell death, and the efficacy of chemotherapy in four independent transplantable tumor models. Adoptive transfer of γδ T cells restored the efficacy of chemotherapy in IL-17A-/- hosts. The anticancer effect of infused γδ T cells was lost when they lacked either IL-1R1 or IL-17A. Conventional helper CD4+ αβ T cells failed to produce IL-17 after chemotherapy. We conclude that γδ T17 cells play a decisive role in chemotherapy-induced anticancer immune responses. © 2011 Ma et al.

Viaud S.,French Institute of Health and Medical Research | Viaud S.,Faculte Of Medecine Of Luniversite Paris Sud Xi | Ploix S.,French Institute of Health and Medical Research | Lapierre V.,French Institute of Health and Medical Research | And 18 more authors.
Journal of Immunotherapy | Year: 2011

Dendritic cell-derived exosomes (Dex) are nanovesicles bearing major histocompatibility complexes promoting T-cell-dependent antitumor effects in mice. Two phase I clinical trials aimed at vaccinating cancer patients with peptide-pulsed Dex have shown the feasibility and safety of inoculating clinical-grade Dex, but have failed to show their immunizing capacity. These low immunogenic capacities have led us to develop second-generation Dex with enhanced immunostimulatory properties. Here, we show that interferon-γ is a key cytokine conditioning the dendritic cell to induce the expression of CD40, CD80, CD86, and CD54 on Dex, endowing them with direct and potent peptide-dependent CD8 T-cell-triggering potential in vitro and in vivo. In this study, we describe the clinical grade process to manufacture large-scale interferon-γ-Dex vaccines and their quality control parameters currently used in a phase II trial. © 2010 by Lippincott Williams & Wilkins.

PubMed | Faculte Of Medecine Of Luniversite Paris Sud Xi
Type: Clinical Trial, Phase I | Journal: Cancer research | Year: 2011

Low doses of the alkylating agent cyclophosphamide (CTX) mediate antiangiogenic and immunostimulatory effects, leading to potent tumoricidal activity in association with various immunotherapeutic strategies. Here, we show in rodents and cancer patients that CTX markedly promotes the differentiation of CD4(+) T helper 17 (Th17) cells that can be recovered in both blood and tumor beds. However, CTX does not convert regulatory T cells into Th17 cells. Because Th17 are potent inducers of tissue inflammation and autoimmunity, these results suggest impact on the clinical management of various types of malignancies treated with alkylating agents and a potential need to optimize CTX-based immunotherapy in patients.

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