Ecully, France
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PubMed | Sahlgrenska University Hospital, Gothenburg University and Orega Biotech
Type: Journal Article | Journal: Cancer immunology research | Year: 2016

T cell-mediated immunity is a major component of antitumor immunity. In order to be efficient, effector T cells must leave the circulation and enter into the tumor tissue. Regulatory T cells (Treg) from gastric cancer patients, but not from healthy volunteers, potently inhibit migration of conventional T cells through activated endothelium. In this study, we compared T cells from colon cancer patients and healthy donors to determine the mechanisms used by Tregs from cancer patients to inhibit conventional T-cell migration. Our results showed that circulating Tregs from cancer patients expressed high levels of CD39, an ectoenzyme mediating hydrolysis of ATP to AMP, as a rate-determining first step in the generation of immunosuppressive adenosine. Tumor-associated Tregs expressed even more CD39, and we therefore examined the importance of adenosine in Treg-mediated inhibition of T-cell transendothelial migration in vitro. Exogenous adenosine significantly reduced migration of conventional T cells from healthy volunteers, and blocking either adenosine receptors or CD39 enzymatic activity during transmigration restored the ability of conventional T cells from cancer patients to migrate. Adenosine did not directly affect T cells or endothelial cells, but reduced the ability of monocytes to activate the endothelium. Taken together, our results indicate that Treg-derived adenosine acts on monocytes and contributes to reduced transendothelial migration of effector T cells into tumors. This effect of Tregs is specific for cancer patients, and our results indicate that Tregs may affect not only T-cell effector functions but also their migration into tumors.


Boer M.C.,Leiden University | Van Meijgaarden K.E.,Leiden University | Bastid J.,Orega Biotech | Ottenhoff T.H.M.,Leiden University | Joosten S.A.,Leiden University
European Journal of Immunology | Year: 2013

Regulatory T (Treg) cells can balance normal tissue homeostasis by limiting inflammatory tissue damage, e.g. during pathogen infection, but on the other hand can also limit protective immunity induced during natural infection or following vaccination. Because most studies have focused on the role of CD4+ Treg cells, relatively little is known about the phenotype and function of CD8+ Treg cells, particularly in infectious diseases. Here, we describe for the first time the expression of CD39 (E-NTPDase1) on Mycobacterium-activated human CD8+ T cells. These CD8+CD39+ T cells significantly co-expressed the Treg markers CD25, Foxp3, lymphocyte activation gene-3 (LAG-3), and CC chemokine ligand 4 (CCL4), and suppressed the proliferative response of antigen-specific CD4+ T helper-1 (Th1) cells. Pharmacological or antibody mediated blocking of CD39 function resulted in partial reversal of suppression. These data identify CD39 as a novel marker of human regulatory CD8+ T cells and indicate that CD39 is functionally involved in suppression by CD8+ Treg cells. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Over the past decade, much effort has been made to understand how cancers metastasize. In deciphering the metastatic process, a vast amount of work has focused on the role of the epithelial to mesenchymal transition (EMT), which, in experimental models, confers tumor cells with invasive and metastatic abilities, resistance to therapies, as well as cancer stem cell phenotype-properties that have a major impact on cancer prognosis. Searching "EMT and cancer" in PubMed retrieves thousands of original research articles, yet, we haven't answered the most basic question in the field: has EMT any relevance in human tumors? © 2011 Springer Science+Business Media, LLC.


Bastid J.,Orega Biotech | Cottalorda-Regairaz A.,Orega Biotech | Alberici G.,Orega Biotech | Bonnefoy N.,University of Lyon | And 6 more authors.
Oncogene | Year: 2013

Regulatory T cells (Tregs) are a subpopulation of CD4 + T cells that are essential for maintaining the homeostasis of the immune system, limiting self-reactivity and excessive immune responses against foreign antigens. In cancer, infiltrated Tregs inhibit the effector lymphocytes and create a favorable environment for the growth of the tumor. Although Tregs mediate immunosuppression through multiple, non-redundant, cell-contact dependent and independent mechanisms, a growing body of evidence suggests an important role for the CD39-CD73-adenosine pathway. CD39 ectonucleotidase is the rate-limiting enzyme of a cascade leading to the generation of suppressive adenosine that alters CD4 and CD8 T cell and natural killer cell antitumor activities. Here, we review the recent literature supporting CD39 as a promising therapeutic target in oncology. In vitro and in vivo experiments involving knockout models and surrogate inhibitors of CD39 provide evidence in support of the anticancer activity of CD39 inhibition and predict a favorable safety profile for CD39 inhibitory compounds. In addition, we report the ongoing development of CD39-blocking monoclonal antibodies as potential anticancer drugs. Indeed, CD39 antagonistic antibodies could represent novel therapeutic tools for selectively inhibiting Treg function without depletion, a major limitation of current Treg-targeting strategies. © 2013 Macmillan Publishers Limited. All rights reserved.


Bonnefoy N.,Montpellier University | Bastid J.,Orega Biotech | Alberici G.,Orega Biotech | Bensussan A.,University Paris Diderot | And 2 more authors.
OncoImmunology | Year: 2015

We report that CD39-expressing-melanoma cells inhibited both T-cell proliferation and the generation of cytotoxic effectors in an adenosine-dependent manner, and that treatment with a CD39-blocking antibody alleviated tumor-mediated immunosuppression. Thus, blocking CD39 ectonucleotidase may represent a novel immunotherapeutic strategy to restore antitumor immunity. © 2015 Taylor & Francis Group, LLC.


Patent
French Institute of Health, Medical Research and Orega Biotech | Date: 2013-01-11

The invention relates generally to methods of treating and/or preventing proliferative diseases, such as cancers, using antagonists of IL-17. The invention also relates to methods and kits for identifying subjects who are likely to respond to treatment and/or prevention of proliferative diseases with antagonists of IL-17.


Patent
Orega Biotech | Date: 2011-12-21

Disclosed are CD39 antagonists that can inhibit the immunosuppressive effect of a CD39-expressing cancerous cell, and methods of using the CD39 antagonists.


Patent
Orega Biotech | Date: 2013-06-11

The invention relates to antagonists of IL-17 isoforms and their uses in diagnosis and therapy, especially for the treatment or prevention of cancers or autoimmune and chronic inflammatory diseases.


Patent
Orega Biotech | Date: 2013-06-25

The disclosure relates to antibodies against human IL-17 which act as antagonist antagonists of IL-17, and their use in the diagnosis or treatment of IL-17 mediated diseases.


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