Publications by authors named "Armand Bensussan"

175 Publications

[Skin aging: Pathophysiology and innovative therapies].

Med Sci (Paris) 2020 Dec 9;36(12):1163-1172. Epub 2020 Dec 9.

Inserm U976 ; Centre de recherche sur la peau ; hôpital Saint-Louis, Paris, France - Service de dermatologie, hôpital Saint Louis, Paris, France.

One of the major challenges of the 21 century is the fight against aging, defined as a set of physiological mechanisms altering the physical and intellectual capacities of human beings. Aging of the skin is only one visible part of this process. It is associated with major healing defects linked in part to the alteration of the biomechanical properties of skin cells, mainly dermal fibroblasts. The immune system, another key component in maintaining skin homeostasis and the efficient healing of wounds, also suffers the effects of time: the consequent skin immunosenescence would limit the anti-infectious and vaccine response, while promoting a pro-tumor environment. The main skin damages due to aging, whether intrinsic or extrinsic, will be detailed before listing the effective anti-aging strategies to combat age-related dermal and epidermal stigmas.
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http://dx.doi.org/10.1051/medsci/2020232DOI Listing
December 2020

ICOS is widely expressed in cutaneous T-cell lymphoma, and its targeting promotes potent killing of malignant cells.

Blood Adv 2020 Oct;4(20):5203-5214

Centre de Recherche en Cancérologie de Marseille, INSERM U1068, Centre National de la Recherche Scientifique U7258, Aix Marseille Université, Institut Paoli-Calmettes, Marseille, France.

The treatment of advanced-stage cutaneous T-cell lymphoma (CTCL) remains an unmet medical need. Mogamulizumab, anti-KIR3DL2, and brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate (ADC) coupled with monomethyl-auristatin-E (MMAE), provided encouraging results, but new targeted therapies are needed. Inducible T-cell costimulator (ICOS), a T-cell costimulatory receptor, is a promising therapeutic target, not only because it is expressed by malignant T cells in CTCL but also because of its connection with the suppressive activity of regulatory T (Treg) cells. Immunohistochemical analysis revealed that ICOS was widely expressed by malignant cells in skin biopsy specimens from 52 patients with mycosis fungoides and Sézary syndrome (SS), as well as in involved node biopsy specimens from patients with SS. Furthermore, flow cytometry demonstrated its strong expression by circulating tumor cells in all our patients with SS. Percentages of ICOS+ Treg cells were significantly higher in patients with SS than in healthy donors. We then investigated the preclinical efficacy of anti-ICOS ADCs generated by coupling murine anti-ICOS monoclonal antibodies with MMAE and pyrrolobenzodiazepine. In 3 CTCL cell lines (Myla, MJ, and HUT78), we observed a significant dose-dependent decrease in cell viability in the presence of anti-ICOS ADCs. In addition, anti-ICOS-MMAE ADCs had an in vitro and in vivo efficacy superior to BV in a mouse xenograft model (MyLa). Finally, we assessed the efficacy of anti-ICOS ADCs in ICOS+ patient-derived xenografts from patients with SS and angioimmunoblastic T-cell lymphoma. Collectively, our findings provide the preliminary basis for a therapeutic trial.
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http://dx.doi.org/10.1182/bloodadvances.2020002395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594390PMC
October 2020

Expansion of Circulating CD49bLAG3 Type 1 Regulatory T Cells in Human Chronic Graft-Versus-Host Disease.

J Invest Dermatol 2021 Jan 16;141(1):193-197.e2. Epub 2020 May 16.

INSERM U976, Human Immunology, Pathophysiology and Immunotherapy, Institut de Recherche Saint-Louis, Hôpital Saint-Louis, Paris, France; Institut de Recherche Saint-Louis, Université de Paris, Hôpital Saint-Louis, Paris, France; Service de Dermatologie, AP-HP, Hôpital Saint-Louis, Paris, France.

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http://dx.doi.org/10.1016/j.jid.2020.04.018DOI Listing
January 2021

In vivo anti-MUC1 tumor activity and sequences of high-affinity anti-MUC1-SEA antibodies.

Cancer Immunol Immunother 2020 Jul 26;69(7):1337-1352. Epub 2020 Mar 26.

School of Molecular Cell Biology and Biotechnology, Tel Aviv University, 69978, Ramat Aviv, Israel.

Cleavage of the MUC1 glycoprotein yields two subunits, an extracellular alpha-subunit bound to a smaller transmembrane beta-subunit. Monoclonal antibodies (mAbs) directed against the MUC1 alpha-beta junction comprising the SEA domain, a stable cell-surface moiety, were generated. Sequencing of all seven anti-SEA domain mAbs showed that they clustered into four groups and sequences of all groups are presented here. mAb DMB5F3 with picomolar affinity for the MUC1 SEA target was selected for further evaluation. Immunohistochemical staining of a series of malignancies with DMB5F3 including lung, prostate, breast, colon, and pancreatic carcinomas revealed qualitative and qualitative differences between MUC1 expression on normal versus malignant cells: DMB5F3 strongly stained malignant cells in a near-circumferential pattern, whereas MUC1 in normal pancreatic and breast tissue showed only weak apical positivity of ductal/acinar cells. Humanized chimeric DMB5F3 linked to ZZ-PE38 (ZZ IgG-binding protein fused to Pseudomonas exotoxin) induced vigorous cytotoxicity of MUC1 malignant cells in vitro. The intensity of cell killing correlated with the level of MUC1 expression by the target cell, suggesting a MUC1 expression threshold for cell killing. MUC1 Colo357 pancreatic cancer cells xenotransplanted into nude and SCID mice models were treated with the chDMB5F3:ZZ-PE38 immunocomplex. In both transplant models, chDMB5F3:ZZ-PE38 exhibited significant in vivo anti-tumor activity, suppressing up to 90% of tumor volume in the SCID model compared with concomitant controls. The efficacy of chDMB5F3:ZZ-PE38 immunotoxin in mediating tumor killing both in vitro and in vivo strongly suggests a clinical role for anti-MUC1 SEA antibody in the treatment of MUC1-expressing malignancies.
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http://dx.doi.org/10.1007/s00262-020-02547-2DOI Listing
July 2020

[A new generation of immunotherapies targeting the CD39/CD73/adenosine pathway to promote the anti-tumor immune response].

Med Sci (Paris) 2020 Feb 4;36(2):112-115. Epub 2020 Mar 4.

Institut de recherche en cancérologie de Montpellier, Inserm U1194, université de Montpellier, institut régional du cancer de Montpellier, 34298 Montpellier, France - OREGA Biotech, 69130 Ecully, France.

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http://dx.doi.org/10.1051/medsci/2020006DOI Listing
February 2020

Persistent deficiency of mucosal-associated invariant T cells during dermatomyositis.

Rheumatology (Oxford) 2020 09;59(9):2282-2286

Université de Paris, Inserm U976 - HIPI Unit, Institut de Recherche Saint-Louis.

Objectives: Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are important for antibacterial immunity and may have regulatory roles. MAIT cells are decreased during SLE. However, their frequencies and phenotype have not been investigated in DM. We studied MAIT cell frequencies and phenotype in DM patients with active and inactive disease (after treatment).

Methods: Peripheral blood flow cytometry analysis of MAIT cells was compared between DM (n = 22), SLE (n = 10), psoriasis (n = 7) and atopic dermatitis (n = 5) patients, and healthy controls (n = 19).

Results: A dramatic decrease of circulating MAIT cell frequency was observed in active DM and SLE patients compared with healthy controls and other inflammatory skin diseases [active DM: median = 0.25% (interquartile range 0.19-0.6%), P < 0.0001; active SLE: median = 0.61 (0.55-0.77), P < 0.0001 vs healthy controls: 2.32% (1.18-4.45%)]. MAIT cells from active DM patients had an abnormal phenotype including increased expression of CD25 and cytotoxic T-lymphocyte-associated protein 4 that correlated with their low frequency in the blood.

Conclusion: In DM, peripheral blood MAIT cells are dramatically reduced and have an activated/exhausted phenotype that may be linked to increased activation-induced cell death.
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http://dx.doi.org/10.1093/rheumatology/kez564DOI Listing
September 2020

Increased CD8CD28 circulating T cells and high blood interferon score characterize the systemic inflammation of amyopathic dermatomyositis.

J Am Acad Dermatol 2019 Nov 22. Epub 2019 Nov 22.

Université de Paris, Inserm U976 - HIPI Unit, Institut de Recherche Saint-Louis, F-75010 Paris, France; Dermatology department, AP-HP, Hôpital Saint-Louis, F-75010 Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2019.11.036DOI Listing
November 2019

Atypical and Mutations in Mucosal Melanoma.

Cancers (Basel) 2019 Aug 8;11(8). Epub 2019 Aug 8.

INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010 Paris, France.

Primary mucosal melanomas represent a minority of melanomas, but have a significantly worse prognosis than cutaneous melanomas. A better characterization of the molecular pathogenesis of this melanoma subtype could help us understand the risk factors associated with the development of mucosal melanomas and highlight therapeutic targets. Because the Mitogen-Activated Protein Kinase (MAPK) pathway plays such a significant role in melanoma development, we explore v-raf murine sarcoma viral oncogene homolog B ( and neuroblastoma RAS viral oncogene homolog ( mutations in mucosal melanoma and compare them to the mutation profiles in cutaneous melanoma and other tumors with and mutations. We show that in addition to being less frequent, and mutations are different in mucosal melanoma compared to cutaneous melanomas. Strikingly, the and mutation profiles in mucosal melanoma are closer to those found in cancers such as lung cancer, suggesting that mutations in mucosal melanoma could be linked to some genotoxic agents that remain to be identified. We also show that the atypical and mutations found in mucosal melanomas have particular effects on protein activities, which could be essential for the transformation of mucosal melanocytes.
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http://dx.doi.org/10.3390/cancers11081133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721527PMC
August 2019

IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial.

Lancet Oncol 2019 08 25;20(8):1160-1170. Epub 2019 Jun 25.

Stanford Cancer Institute, Stanford, CA, USA.

Background: IPH4102 is a first-in-class monoclonal antibody targeting KIR3DL2, a cell surface protein that is expressed in cutaneous T-cell lymphoma, and predominantly in its leukaemic form, Sézary syndrome. We aimed to assess the safety and activity of IPH4102 in cutaneous T-cell lymphoma.

Methods: We did an international, first-in-human, open-label, phase 1 clinical trial with dose-escalation and cohort-expansion parts in five academic hospitals in the USA, France, the UK, and the Netherlands. Eligible patients had histologically confirmed relapsed or refractory primary cutaneous T-cell lymphoma, an Eastern Cooperative Oncology group performance score of 2 or less, were aged 18 years or older, and had received at least two previous systemic therapies. Ten dose levels of IPH4102, administered as an intravenous infusion, ranging from 0·0001 mg/kg to 10 mg/kg, were assessed using an accelerated 3 + 3 design. The primary endpoint was the occurrence of dose-limiting toxicities during the first 2 weeks of treatment, defined as toxicity grade 3 or worse lasting for 8 or more days, except for lymphopenia. Global overall response by cutaneous T-cell lymphoma subtype was a secondary endpoint. Safety and activity analyses were done in the per-protocol population. The study is ongoing and recruitment is complete. This trial is registered with ClinicalTrials.gov, number NCT02593045.

Findings: Between Nov 4, 2015, and Nov 20, 2017, 44 patients were enrolled. 35 (80%) patients had Sézary syndrome, eight (18%) had mycosis fungoides, and one (2%) had primary cutaneous T-cell lymphoma, not otherwise specified. In the dose-escalation part, no dose limiting toxicity was reported and the trial's safety committee recommended a flat dose of 750 mg for the cohort-expansion, corresponding to the maximum administered dose. The most common adverse events were peripheral oedema (12 [27%] of 44 patients) and fatigue (nine [20%]), all of which were grade 1-2. Lymphopenia was the most common grade 3 or worse adverse event (three [7%]). One patient developed possibly treatment-related fulminant hepatitis 6 weeks after IPH4102 discontinuation and subsequently died. However, the patient had evidence of human herpes virus-6B infection. Median follow-up was 14·1 months (IQR 11·3-20·5). A confirmed global overall response was achieved in 16 (36·4% [95% CI 23·8-51·1]) of 44 patients, and of those, 15 responses were observed in 35 patients with Sézary syndrome (43% [28·0-59·1]).

Interpretation: IPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sézary syndrome. If confirmed in future trials, IPH4102 could become a novel treatment option for these patients. A multi-cohort, phase 2 trial (TELLOMAK) is underway to confirm the activity in patients with Sézary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2.

Funding: Innate Pharma.
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http://dx.doi.org/10.1016/S1470-2045(19)30320-1DOI Listing
August 2019

Blocking Antibodies Targeting the CD39/CD73 Immunosuppressive Pathway Unleash Immune Responses in Combination Cancer Therapies.

Cell Rep 2019 05;27(8):2411-2425.e9

IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, 34298 Montpellier, France. Electronic address:

Immune checkpoint inhibitors have revolutionized cancer treatment. However, many cancers are resistant to ICIs, and the targeting of additional inhibitory signals is crucial for limiting tumor evasion. The production of adenosine via the sequential activity of CD39 and CD73 ectoenzymes participates to the generation of an immunosuppressive tumor microenvironment. In order to disrupt the adenosine pathway, we generated two antibodies, IPH5201 and IPH5301, targeting human membrane-associated and soluble forms of CD39 and CD73, respectively, and efficiently blocking the hydrolysis of immunogenic ATP into immunosuppressive adenosine. These antibodies promoted antitumor immunity by stimulating dendritic cells and macrophages and by restoring the activation of T cells isolated from cancer patients. In a human CD39 knockin mouse preclinical model, IPH5201 increased the anti-tumor activity of the ATP-inducing chemotherapeutic drug oxaliplatin. These results support the use of anti-CD39 and anti-CD73 monoclonal antibodies and their combination with immune checkpoint inhibitors and chemotherapies in cancer.
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http://dx.doi.org/10.1016/j.celrep.2019.04.091DOI Listing
May 2019

Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit.

Stem Cells Transl Med 2019 09 28;8(9):911-924. Epub 2019 Mar 28.

Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-976, Université Paris-Diderot, Hôpital Saint-Louis, Paris, France.

The positive effects of therapeutic human allogeneic cardiac stem/progenitor cells (hCPC) in terms of cardiac repair/regeneration are very likely mediated by paracrine effects. Our previous studies revealed the advantageous immune interactions of allogeneic hCPC and proposed them as part of the positive paracrine effects occurring upon their application postmyocardial infarction (MI). Currently, extracellular vesicles/exosomes (EV/Exs) released by stem/progenitor cells are also proposed as major mediators of paracrine effects of therapeutic cells. Along this line, we evaluated contribution of EV/Exs released by therapeutic hCPC to the benefit of their successful allogeneic clinical application. Through tailored allogeneic in vitro human assay models mimicking the clinical setting, we demonstrate that hCPC-released EV/Exs were rapidly and efficiently up-taken by chief cellular actors of cardiac repair/regeneration. This promoted MAPK/Erk1/2 activation, migration, and proliferation of human leukocyte antigens (HLA)-mismatched hCPC, mimicking endogenous progenitor cells and cardiomyocytes, and enhanced endothelial cell migration, growth, and organization into tube-like structures through activation of several signaling pathways. EV/Exs also acted as pro-survival stimuli for HLA-mismatched monocytes tuning their phenotype toward an intermediate anti-inflammatory pro-angiogenic phenotype. Thus, while positively impacting the intrinsic regenerative and angiogenic programs, EV/Exs released by therapeutic allogeneic hCPC can also actively contribute to shaping MI-inflammatory environment, which could strengthen the benefits of hCPC allogeneic interactions. Collectively, our data might forecast the application of allogeneic hCPC followed by their cell-free EV/Exs as a strategy that will not only elicit the cell-contact mediated reparative/regenerative immune response but also have the desired long-lasting effects through the EV/Exs. Stem Cells Translational Medicine 2019;8:911&924.
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http://dx.doi.org/10.1002/sctm.18-0256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708067PMC
September 2019

Microenvironment tailors nTreg structure and function.

Proc Natl Acad Sci U S A 2019 03 7;116(13):6298-6307. Epub 2019 Mar 7.

Laboratory of Oncodermatology, Immunology, and Cutaneous Stem Cells, INSERM U976, 75010 Paris, France.

Natural regulatory T cells (nTregs) ensure the control of self-tolerance and are currently used in clinical trials to alleviate autoimmune diseases and graft-versus-host disease after hematopoietic stem cell transfer. Based on CD39/CD26 markers, blood nTreg analysis revealed the presence of five different cell subsets, each representing a distinct stage of maturation. Ex vivo added microenvironmental factors, including IL-2, TGFβ, and PGE2, direct the conversion from naive precursor to immature memory and finally from immature to mature memory cells, the latest being a no-return stage. Phenotypic and genetic characteristics of the subsets illustrate the structural parental maturation between subsets, which further correlates with the expression of regulatory factors. Regarding nTreg functional plasticity, both maturation stage and microenvironmental cytokines condition nTreg activities, which include blockade of autoreactive immune cells by cell-cell contact, Th17 and IL-10 Tr1-like activities, or activation of TCR-stimulating dendritic cell tolerization. Importantly, blood nTreg CD39/CD26 profile remained constant over a 2-y period in healthy persons but varied from person to person. Preliminary data on patients with autoimmune diseases or acute myelogenous leukemia illustrate the potential use of the nTreg CD39/CD26 profile as a blood biomarker to monitor chronic inflammatory diseases. Finally, we confirmed that naive conventional CD4 T cells, TCR-stimulated under a tolerogenic conditioned medium, could be ex vivo reprogrammed to FOXP3 lineage Tregs, and further found that these cells were exclusively committed to suppressive function under all microenvironmental contexts.
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http://dx.doi.org/10.1073/pnas.1812471116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442590PMC
March 2019

Identification of CD39 as a Marker for the Circulating Malignant T-Cell Clone of Sézary Syndrome Patients.

J Invest Dermatol 2019 03 25;139(3):725-728. Epub 2018 Oct 25.

INSERM U976, Oncodermatology, Immunology and Cutaneous stem cells, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2018.09.026DOI Listing
March 2019

Soluble Fc-Disabled Herpes Virus Entry Mediator Augments Activation and Cytotoxicity of NK Cells by Promoting Cross-Talk between NK Cells and Monocytes.

J Immunol 2019 04 15;202(7):2057-2068. Epub 2019 Feb 15.

Department of Dermatology, Case Western Reserve University School of Medicine, Cleveland, OH 44106;

CD160 is highly expressed by NK cells and is associated with cytolytic effector activity. Herpes virus entry mediator (HVEM) activates NK cells for cytokine production and cytolytic function via CD160. Fc-fusions are a well-established class of therapeutics, where the Fc domain provides additional biological and pharmacological properties to the fusion protein including enhanced serum and interaction with Fc receptor-expressing immune cells. We evaluated the specific function of HVEM in regulating CD160-mediated NK cell effector function by generating a fusion of the HVEM extracellular domain with human IgG1 Fc bearing CD16-binding mutations (Fc*) resulting in HVEM-(Fc*). HVEM-(Fc*) displayed reduced binding to the Fc receptor CD16 (i.e., Fc-disabled HVEM), which limited Fc receptor-induced responses. HVEM-(Fc*) functional activity was compared with HVEM-Fc containing the wild type human IgG1 Fc. HVEM-(Fc*) treatment of NK cells and PBMCs caused greater IFN-γ production, enhanced cytotoxicity, reduced NK fratricide, and no change in CD16 expression on human NK cells compared with HVEM-Fc. HVEM-(Fc*) treatment of monocytes or PBMCs enhanced the expression level of CD80, CD83, and CD40 expression on monocytes. HVEM-(Fc*)-enhanced NK cell activation and cytotoxicity were promoted via cross-talk between NK cells and monocytes that was driven by cell-cell contact. In this study, we have shown that soluble Fc-disabled HVEM-(Fc*) augments NK cell activation, IFN-γ production, and cytotoxicity of NK cells without inducing NK cell fratricide by promoting cross-talk between NK cells and monocytes without Fc receptor-induced effects. Soluble Fc-disabled HVEM-(Fc*) may be considered as a research and potentially therapeutic reagent for modulating immune responses via sole activation of HVEM receptors.
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http://dx.doi.org/10.4049/jimmunol.1801449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424646PMC
April 2019

The Interleukin-17 Family of Cytokines in Breast Cancer.

Int J Mol Sci 2018 Dec 4;19(12). Epub 2018 Dec 4.

Institut Jean Godinot, Unicancer, F-51726 Reims, France.

Breast cancer (BC) is the most common cancer in women worldwide and remains a major cause of mortality with an expected 137,000 death this year in Europe. Standard management of metastatic BC comprises hormonotherapy, chemotherapy, and targeted therapies. Cyclin dependent kinase (CDK) and mammalian target of rapamycin (mTOR) inhibitors have recently proved their efficiency in hormonal receptor expressing BC. Checkpoint proteins inhibition is being evaluated in phase 3 studies. Since inflammation is constantly present in cancers, research teams have focused their attention on the interleukin-17 (IL-17) family of proinflammatory cytokines. Preclinical experiments have reported both pro and antitumor effects depending on the conditions. In the present article, we review the accumulating evidences about the roles of IL-17 in BC and discuss whether this family of cytokines could be a new target in anticancer treatments.
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http://dx.doi.org/10.3390/ijms19123880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321268PMC
December 2018

Increased expression of PD1 and CD39 on CD3 CD4 skin T cells in the elderly.

Exp Dermatol 2019 01;28(1):80-82

INSERM UMRS-976, Saint-Louis Hospital, Paris, France.

Normal ageing is associated with an impaired systemic immune response contributing to an increased susceptibility to infectious diseases. The aim of this study was to compare the lymphocyte phenotype in human skin from old and young healthy subjects. Skin samples from donors were used for explant cultures before flow cytometric analysis. Our results depicted a higher proportion of CD4 and a lower proportion of CD8 among CD3 T cells, a decreased proportion of CD45RA naive T cells (3.5 ± 1.9% vs 22.9 ± 11.1%, P ≤ 0.007) and an upregulation of the expression of CD39 and PD1 on CD3 CD4 T cells (25.1 ± 8.5% vs 12.5 ± 8.5%, P ≤ 0.003, 68.8 ± 11.6% vs 50.0 ± 11.3%, P ≤ 0.01, respectively) in the skin of old subjects. These findings could explain a reduced generation of long-lived memory T cells and an impaired antitumoral response in the skin of the elderly.
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http://dx.doi.org/10.1111/exd.13842DOI Listing
January 2019

Anti-CD160, Alone or in Combination With Bevacizumab, Is a Potent Inhibitor of Ocular Neovascularization in Rabbit and Monkey Models.

Invest Ophthalmol Vis Sci 2018 06;59(7):2687-2698

Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, CNRS UMR 5282, Université Toulouse III, Toulouse, France.

Purpose: To assess the efficacy of the murine first-in-class CL1-R2 monoclonal antibody (mAb) targeting human CD160 (alone or in combination with bevacizumab) by using the rabbit corneal neovascularization (CNV) model, and determine the safety and efficacy of ELB01101, a novel CL1-R2-derived humanized IgG4 mAb, in a monkey model of choroidal neovascularization (ChNV).

Methods: Comparison of effect of CL1-R2, bevacizumab, or aflibercept or IgG1 (control) injections in early and late treatment schemes on evolution of VEGF- or FGF2-induced rabbit CNV was performed. In the combination setting, bevacizumab was coinjected with different doses of CL1-R2. ELB01101 or vehicle was administered intravitreally in monkeys after laser-induced ChNV. Individual laser-induced lesions were semiquantitatively graduated by using fluorescein angiography to determine leakage.

Results: In the rabbit model, early and late treatments with CL1-R2 significantly decreased both area and length of CNV neovessels. The effect was as potent as produced with anti-VEGF comparators. When combined with bevacizumab, an additive effect of CL1-R2 was measured at all doses tested. In the ChNV model, on day 29, eyes treated with ELB01101 showed a statistically significant reduction in clinically relevant lesions compared to vehicle-treated eyes (∼50%; χ2 test, P = 0.032001).

Conclusions: The additive effects of anti-CD160 and bevacizumab in the CNV model suggest that these compounds could act via different pathways, opening new therapeutic pathways for cotargeted or combination therapies. In the ChNV model, ELB01101 was well tolerated and prevented approximately 50% of clinically relevant lesions, validating CD160 targeting as a safe approach for treatment of retinal diseases in the most relevant animal model of wet AMD.
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http://dx.doi.org/10.1167/iovs.18-24024DOI Listing
June 2018

CD160 Expression in Retinal Vessels Is Associated With Retinal Neovascular Diseases.

Invest Ophthalmol Vis Sci 2018 06;59(7):2679-2686

Department of Ophthalmology, Hôpital Robert Debré, Reims, France.

Purpose: Anti-angiogenic agents stand first in the treatment of neovascular diseases of the retina. CD160 appeared in several experimental studies as a marker of activated endothelial cells, suggesting it could represent a promising target for novel anti-angiogenic therapies. The aim of the present study was to assess the distribution of CD160 in the human eye, and to search for a possible correlation with retinal neovascular diseases.

Methods: The physiological distribution of CD160 in the normal eye was assessed with immunolabeling in 10 human donor eyes. Then, in a retrospective cohort of 75 surgical retinal specimens, the density of CD160+ microvessels was evaluated, along with immunolabeling on serial sections against ERG (pan-endothelial cell marker), CD105 (activated endothelial cell marker), and α-SMA (pericyte cell marker). The cohort was divided into two groups: 29 patients with neovascular disease (NV+) and 46 control patients (NV-).

Results: CD160 was physiologically expressed by several cell types: endothelial cells of retinal blood vessels, ganglion cells, macrophages, epithelial cells of the conjunctiva, ciliary body, and retinal pigment epithelium. In the patient cohort, the percentage of CD160+ vessels in the retina was significantly and independently higher in patients suffering from neovascular diseases (P = 0.04). On the contrary, the expression of CD105 was correlated neither with retinal neovascular diseases, nor with CD160 expression.

Conclusions: CD160 was expressed in some retinal vessels in both normal and pathologic eyes. CD160 expression by endothelial cells of retinal vessels was correlated with ocular neovascular diseases. CD160 could therefore represent an interesting target for novel anti-angiogenic therapies.
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http://dx.doi.org/10.1167/iovs.18-24021DOI Listing
June 2018

Triple-negative and HER2-overexpressing breast cancer cell sialylation impacts tumor microenvironment T-lymphocyte subset recruitment: a possible mechanism of tumor escape.

Cancer Manag Res 2018 4;10:1051-1059. Epub 2018 May 4.

INSERM U976; Université Paris Diderot, Sorbonne Paris Cité, Laboratory of Immunology, Dermatology & Oncology, Paris, France.

Introduction: Breast cancers develop different patterns of sialylation to modulate their tumor-infiltrating lymphocyte (TIL) environment. We studied the relationship between α-2,6 sialyltransferases and the TIL in different breast cancer molecular subgroups.

Materials And Methods: Immunohistochemical preparations were made from 39 luminal (LUM), 13 human epidermal growth factor receptor 2-overexpressing (HER2) and 47 triple-negative (TN) breast carcinomas. Targeted proteins included ST6Gal-I, ST6Gal-II, ST6GalNac-I, CD8, CD4 and granzyme-B in both cytotoxic T lymphocytes and NK lymphocytes (CTL/NK).

Results: CTL/NK populations were significantly more frequent in TN than LUM ( <0.001). TN showed a lower level of ST6Gal-I expression than LUM or HER2 (both > 0.001). ST6GalNac-I expression was lower in LUM than in TN or HER2 ( = 0.002 and = 0.02, respectively). In HER2, a significant association was found between a low level of ST6Gal-I expression and a high TIL level. In TN, a significant association was observed between a high level of ST6Gal-II expression and a high TIL level.

Conclusion: An increase in infiltrating lymphocytes could be influenced by low expression of ST6Gal-I in HER2 and by high expression of ST6Gal-II in TN breast cancers. Thus, targeting these sialylation pathways could modulate the levels of TIL.
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http://dx.doi.org/10.2147/CMAR.S162932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942397PMC
May 2018

Impact of prednisone in patients with repeated embryo implantation failures: Beneficial or deleterious?

J Reprod Immunol 2018 06 26;127:11-15. Epub 2018 Mar 26.

Institut National de Santé et de Recherche Médicale, INSERM UMR-976, Saint-Louis Hospital, Research Center, 1 Avenue Claude Vellefaux, 75010, Paris, France.

Introduction: Corticotherapy is the leading medication worldwide for patients with history of repeated implantation failures (RIF) after IVF/ICSI. Nevertheless, we still do not know its local mechanism of action, hence its precise indication. Our objective is to document the impact of prednisone on the endometrial expression of immune biomarkers (CD56 cells count, IL-18/TWEAK, IL-15/Fn-14 mRNA ratio) at the time of uterine receptivity in a RIF population.

Materials And Method: An endometrial biopsy was realized in the mid luteal phase for immune profiling: IL-15/Fn-14 and IL-18/TWEAK mRNA ratios were determined by quantitative RT-PCR and CD56 mobilization per IHC. Fifty-five patients with a RIF history were diagnosed to have local over-immune activation [high IL-18/TWEAK mRNA ratio, and/or high IL-15/Fn-14 mRNA ratio] likely to impair the implantation process. They underwent a second immune profiling with supplementation of prednisone. A paired comparison of the immune profile before and under prednisone was performed in the subset of patients subsequently pregnant under prednisone.

Finding: In 54.5% of the cases, both immune biomarkers were normalized and in 16.5%, only one was normalized under prednisone. In 29% we observed a paradoxical increase of both immune biomarkers. The IL-18/TWEAK mRNA ratio reflecting the Th-1/Th-2 local equilibrium was significantly reduced (0.29 versus 0.10, p = .004), through very significant increase of TWEAK expression, in patients who were subsequently pregnant under prednisone.

Conclusion: Testing the response to prednisone in a RIF context may be very useful. Less than half of RIF patients with immune deregulation may be prednisone responders and would benefit from its administration.
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http://dx.doi.org/10.1016/j.jri.2018.03.003DOI Listing
June 2018

The IL-17B-IL-17 receptor B pathway promotes resistance to paclitaxel in breast tumors through activation of the ERK1/2 pathway.

Oncotarget 2017 Dec 6;8(69):113360-113372. Epub 2017 Dec 6.

IRCM, INSERM, Université de Montpellier, ICM, Montpellier, F-34298 France.

Interleukin 17B (IL-17B) is a pro-inflammatory cytokine that belongs to the IL-17 cytokines family and binds to IL-17 receptor B (IL-17RB). Here we found that high expression of IL-17B and IL-17RB is associated with poor prognosis in patients with breast cancer and that IL-17B expression upregulation is specifically associated with poorer survival in patients with basal-like breast cancer. We thus focused on IL-17B role in breast cancer by using luminal and triple negative (TN)/basal-like tumor cell lines. We found that IL-17B induces resistance to conventional chemotherapeutic agents. , IL-17B induced resistance to paclitaxel and treatment with an anti-IL-17RB neutralizing antibody completely restored breast tumor chemosensitivity, leading to tumor shrinkage. We next focused on the signaling pathways activated in human breast cancer cell lines upon incubation with IL-17B. We observed that IL-17B induces ERK1/2 pathway activation, leading to upregulation of anti-apoptotic proteins of the BCL-2 family. IL-17B-induced chemoresistance was completely abolished by incubation with PD98059, an inhibitor of the MAPK/ERK pathway, indicating that the ERK pathway plays a crucial role. Altogether our results emphasize the role of the IL-17B/IL-17RB signaling pathway in breast tumors and identify IL-17B and its receptor as attractive therapeutic targets for potentiating breast cancer chemotherapy.
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http://dx.doi.org/10.18632/oncotarget.23008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768333PMC
December 2017

Truncating mutations of TP53AIP1 gene predispose to cutaneous melanoma.

Genes Chromosomes Cancer 2018 Jun 21;57(6):294-303. Epub 2018 Feb 21.

INSERM U976, Centre de Recherche sur la Peau, Hôpital Saint Louis, 75010, Paris, France.

Genetic predisposition to cutaneous malignant melanoma (CMM) involves highly penetrant predisposing genes and low and intermediate penetrant predisposing alleles. However, the missing heritability in (CMM) is still high. For such and in order to identify new genetic factors for CMM, we conducted an exome sequencing study in high-risk CMM patients. Two rounds of exome sequencing were successively performed in 33 and 27 high-risk patients. We focused on genes carrying rare nonsense, frameshift, and splice variants (allelic frequency <1%) that were present in both series of exomes. An extension study was then conducted in a large cohort (1 079 CMM patients and 1 230 Caucasian ethnically matched healthy controls), and the inactivating variants frequency was compared between groups using two-sided Fisher exact test. Two TP53AIP1 truncating mutations were identified in four patients: a frameshift c.63_64insG, p.Q22Afs*81 in two patients from the same family and in the proband of a second family; and a nonsense mutation c.95 C > A, p.Ser32Stop in a patient with multiple CMMs. In all patients, TP53AIP1 truncating variants were strongly associated with CMM risk (two-sided Fisher exact test = 0.004, OR = 3.3[1.3-8.5]). Additionally, we showed that TP53AIP1 mRNA was strongly down-regulated throughout different phases of melanoma progression. TP53AIP1 gene is a TP53 target which plays a key role by inducting apoptosis in response to UV-induced DNA damage. Constitutional mutations of TP53AIP1 had previously been involved in susceptibility to prostate cancer. Our results show that constitutional truncating TP53AIP1 mutations predispose to CMM in the French population. Replication studies in other populations should be performed.
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http://dx.doi.org/10.1002/gcc.22528DOI Listing
June 2018

Human Cardiac-Derived Stem/Progenitor Cells Fine-Tune Monocyte-Derived Descendants Activities toward Cardiac Repair.

Front Immunol 2017 26;8:1413. Epub 2017 Oct 26.

Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS-976, Université Paris-Diderot, Hôpital Saint-Louis, Paris, France.

Cardiac repair following MI relies on a finely regulated immune response involving sequential recruitment of monocytes to the injured tissue. Monocyte-derived cells are also critical for tissue homeostasis and healing process. Our previous findings demonstrated the interaction of T and natural killer cells with allogeneic human cardiac-derived stem/progenitor cells (hCPC) and suggested their beneficial effect in the context of cardiac repair. Therefore, we investigated here whether monocytes and their descendants could be also modulated by allogeneic hCPC toward a repair/anti-inflammatory phenotype. Through experimental assays, we assessed the impact of allogeneic hCPC on the recruitment, functions and differentiation of monocytes. We found that allogeneic hCPC at steady state or under inflammatory conditions can incite CCL-2/CCR2-dependent recruitment of circulating CD14CD16 monocytes and fine-tune their activation toward an anti-inflammatory profile. Allogeneic hCPC also promoted CD14CD16 monocyte polarization into anti-inflammatory/immune-regulatory macrophages with high phagocytic capacity and IL10 secretion. Moreover, hCPC bended the differentiation of CD14CD16 monocytes to dendritic cells (DCs) toward anti-inflammatory macrophage-like features and impaired their antigen-presenting function in favor of immune-modulation. Collectively, our results demonstrate that allogeneic hCPC could reshape monocytes, macrophages as well as DCs responses by favoring their anti-inflammatory/tolerogenic activation/polarization. Thereby, therapeutic allogeneic hCPC might also contribute to post-infarct myocardial healing by modeling the activities of monocytes and their derived descendants.
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http://dx.doi.org/10.3389/fimmu.2017.01413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662627PMC
October 2017

KIR3DL2 expression in cutaneous T-cell lymphomas: expanding the spectrum for KIR3DL2 targeting.

Blood 2017 12 31;130(26):2900-2902. Epub 2017 Oct 31.

Pathology Department, Assistance Publique Hôpitaux de Paris Hôpital Saint Louis, Paris, France.

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http://dx.doi.org/10.1182/blood-2017-06-792382DOI Listing
December 2017

Therapeutic Antibodies to KIR3DL2 and Other Target Antigens on Cutaneous T-Cell Lymphomas.

Front Immunol 2017 30;8:1010. Epub 2017 Aug 30.

INSERM U976, Hôpital Saint-Louis, Paris, France.

KIR3DL2 is a member of the killer cell immunoglobulin-like receptor (KIR) family that was initially identified at the surface of natural killer (NK) cells. KIR3DL2, also known as CD158k, is expressed as a disulfide-linked homodimer. Each chain is composed of three immunoglobulin-like domains and a long cytoplasmic tail containing two immunoreceptor tyrosine-based inhibitory motifs. Beside its expression on NK cells, it is also found on rare circulating T lymphocytes, mainly CD8. Although the KIR gene number varies between haplotype, KIR3DL2 is a framework gene present in all individuals. Together with the presence of genomic regulatory sequences unique to KIR3DL2, this suggests some particular functions for the derived protein in comparison with other KIR family members. Several ligands have been identified for KIR3DL2. As for other KIRs, binding to HLA class I molecules is essential for NK development by promoting phenomena such as licensing and driving NK cell maturation. For KIR3DL2, this includes binding to HLA-A3 and -A11 and to the free heavy chain form of HLA-B27. In addition, KIR3DL2 binds to CpG oligonucleotides (ODN) and ensures their transport to endosomal toll-like receptor 9 that promotes cell activation. These characteristics have implicated KIR3DL2 in several pathologies: ankylosing spondylitis and cutaneous T-cell lymphomas such as Sézary syndrome, CD30 cutaneous lymphoma, and transformed mycosis fungoides. Consequently, a new generation of humanized monoclonal antibodies (mAbs) directed against KIR3DL2 has been helpful in the diagnosis, follow-up, and treatment of these diseases. In addition, preliminary clinical studies of a novel targeted immunotherapy for cutaneous T-cell lymphomas using the anti-KIR3DL2 mAb IPH4102 are now underway. In this review, we discuss the various aspects of KIR3DL2 on the functions of CD4 T cells and how targeting this receptor helps to develop innovative therapeutic strategies.
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http://dx.doi.org/10.3389/fimmu.2017.01010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582066PMC
August 2017

Up-and-down immunity of pregnancy in humans.

F1000Res 2017 25;6:1216. Epub 2017 Jul 25.

INSERM U976, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Saint-Louis, Equerre Bazin, 1, Avenue Claude Vellefaux, 75475 Paris Cedex 10, France.

One part of the human placenta in early pregnancy is particularly important for local immunity: the , which is transformed endometrium located at the site of embryo implantation This placental bed tissue contains both maternal uterine immune cells, including decidual natural killer (NK) cells, the dominant leukocyte population exhibiting a unique phenotype, and fetal extravillous trophoblast which comes into direct contact with maternal decidual cells To establish a successful placental development and healthy pregnancy outcome, the maternal immune system must tolerate paternal antigens expressed by trophoblast cells yet remain efficient for clearing any local pathogen infection. This review deals mainly with decidual NK cells. A key element, among others, to achieve such dual functions is the direct interaction between activating and inhibitory receptors expressed by decidual NK cells and their specific ligands presented by trophoblast or other decidual cells. Depending whether maternal decidual cells and trophoblast are infected by viruses, the balance between activating and inhibitory receptor signals mediated by decidual NK cell-trophoblast cross-talk results in tolerance (healthy pregnancy) or specific killing (pathogen-infected cells).
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http://dx.doi.org/10.12688/f1000research.11690.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531158PMC
July 2017