Search

This article makes the case for reading Zola’s protagonists Laurent and Thérèse as literary foils for one of the founding fathers of the experimental method, namely the physiologist Claude Bernard, and his wife, Fanny Martin. Drawing more particularly on elements from Bernard’s and Martin’s lives, as well as Bernard’s scientific writings, the article shows that Zola ‘performs’ two grueling experiments in the aforementioned novel: the first one, initiated by the author himself, results in the death of three protagonists and the paralysis of the fourth one; the second experiment, initiated by Laurent, reveals that the latter’s evaluation of Thérèse and his ensuing hypothesis are seriously flawed. In fact, Laurent’s gaze is marred by his tendency to ‘dirty’ nature (‘salir la nature,’ to borrow Zola’s expression), and his experiment doesn’t turn out the way he had originally planned, as both lovers turned murderers end up committing suicide together. This article thus argues that, in Thérèse Raquin, Zola resorts to critical posturing as a vivisector in a text that can be read as a revenge narrative which gestures towards the possibility for vivisectors to be ‘redeemed’ as individuals made fully capable of feeling compassion for their objects through angelic intervention.

Background: Due to their basal stress phenotype associated to transformation, cancer cells are addicted to non-mutated, non-oncogenic proteins that do not bear such vital functions in normal cells, a phenomenon referred as Non-Oncogenic Addiction (NOA). Targeting these NOAs could therefore induce selective killing of cancer cells, opening several therapeutic opportunities. Recent data suggest that the stress-related scaffold protein AAC-11 (anti-apoptosis clone 11, also known as Api5) is critically involved in cancer cells resistance to chemotherapies, metastatic potential and escape from the immune system. Methods: We have developed inactivating peptides based on the fusion of a cell penetrating sequence and portions of the leucine-zipper domain of AAC-11, which functions as a protein-protein interaction module. These peptides induce cancer cells death, through the inhibition of protein-protein interactions between AAC-11 and its partners, while sparing normal cells. We now describe further characterization of our lead peptide, JRT39, which contains residues 377 to 379 of AAC-11 linked to the cell-penetrating peptide “penetratin”. Results: In vitro, JRT39 causes cell death in a wide spectrum of cancer cell lines with IC50 ranging from 5 µM to 30 µM depending on tumor cell type. In particular, JRT39 showed selective efficacy towards primary cells from Acute Myeloid Leukemia (AML), Acute Lymphocytic Leukemia (ALL) or Sézary syndrome (SS) patients, while sparing normal hematopoietic cells, with an IC50 of 5-15 µM. Mechanistically, JRT39 induces membranolysis of cancer cells through binding to p21-activated kinase 1 (PAK1) in AML or SS cells plasma membrane, where PAK1 is overexpressed. In addition, JRT39 exerted potent anti-tumor activity in vivo in disseminated or subcutaneous AML, APL (Acute Promyelocytic Leukemia) and SS-patient derived preclinical murine models. Preliminary pharmacokinetic studies revealed that JRT39 is stable in human serum and has a plasma half-life of ~1.5-2.5 hours after intravenous (IV) administration to dogs or cynomolgus monkeys, with concentration-time data fitting 2-compartment model. Finally, JRT39 was well tolerated at 5 and 10 mg/kg after single or repeated (daily) IV injections. Conclusions: Combined, our preclinical data confirm that interfering with AAC-11-related survival pathways is a promising novel anticancer strategy and support the development of JRT39 for the treatment of cancer. Citation Format: Louise Jeammet, Emile Adicéam, Justine Habault, Anna Kaci, Jeannig Berrou, Mélanie Dupont, Nicolas Thonnart, Ewa Pasquereau-Kotula, Anne Marie-Cardine, Armand Bensussan, Marika Pla, Hervé Dombret, Claude Gardin, Martine Bagot, Jean-Christophe Rain, Hélène Sicard, Jérôme Tiollier, Thorsten Braun, Jean-Luc Poyet. AAC-11 survival pathways as therapeutic target in cancer: AAC-11 leucine-zipper domain derived peptides exert potent antitumor effects and exhibit favorable stability, pharmacokinetic and toxicology profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 464.

Adult T-cell leukemia (ATL) is a lymphoid neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1), which encodes the transcriptional activator Tax, which participates in the immortalization of infected T cells. ATL is classified into 4 subtypes: smoldering, chronic, acute, and lymphoma. We determined whether natural killer receptors (NKRs) were expressed in ATL. NKR expression (KIR2DL1/2DS1, KIR2DL2/2DL3/2DS2, KIR3DL2, NKG2A, NKG2C, and NKp46) was assessed in a discovery cohort of 21 ATL, and KIR3DL2 was then assessed in 71 patients with ATL. KIR3DL2 was the only NKR among those studied frequently expressed by acute-type vs lymphoma- and chronic/smoldering-type ATL (36 of 40, 4 of 16, and 1 of 15, respectively; P = .001), although acute- and lymphoma-type ATL had similar mutation profiles by targeted exome sequencing. The correlation of KIR3DL2 expression with promoter demethylation was determined by microarray-based DNA methylation profiling. To explore the role of HTLV-1, KIR3DL2 and TAX messenger RNA (mRNA) expression levels were assessed by PrimeFlow RNA in primary ATL and in CD4+ T cells infected with HTLV-1 in vitro. TAX mRNA and KIR3DL2 protein expressions were correlated on ATL cells. HTLV-1 infection triggered KIR3DL2 by CD4+ cells but Tax alone did not induce KIR3DL2 expression. Ex vivo, autologous, antibody-dependent cell cytotoxicity using lacutamab, a first-in-class anti-KIR3DL2 humanized antibody, selectively killed KIR3DL2+ primary ATL cells ex vivo. To conclude, KIR3DL2 expression is associated with acute-type ATL. Transcription of KIR3DL2 may be triggered by HTLV-1 infection and correlates with hypomethylation of the promoter. The benefit of targeting KIR3DL2 with lacutamab is being further explored in a randomized phase 2 study in peripheral T-cell lymphoma, including ATL (registered on https://clinicaltrials.gov as #NCT04984837).

Over the last few years, an increasing number of agricultural R&D actors have sought to discover and get to know farmers’ practices that they consider as innovative, unconventional, or promising. We refer to these approaches, all of which aim to support the design of farming systems, as ‘farmer innovation tracking’. There is still a lack of knowledge, however, about the specificities of the approaches adopted to track innovations and how they contribute to design processes. To explore these questions, we studied 14 initiatives in France led by actors from different R&D networks. We analysed the data collected using agronomy and design science concepts. Three outcomes emerge from this work. (1) We shed light on the common features of innovation tracking. We outline five stages that structure all the approaches: formulating an innovation tracking project, unearthing innovations, learning about them, analysing them, and generating agronomic content. (2) We characterize six contributions of farmer innovation tracking to design processes: giving rise to creative anomalies, shedding light on systemic mechanisms to fuel design processes on other farms, uncovering research questions, stimulating design in orphan fields of innovation, circulating innovation concepts, and connecting farmer-designers with each other. (3) Finally, we highlight three tracking strategies: the targeted tracking of proven practices, the targeted tracking of innovations under development, and the exploratory tracking of proven practices. This article is the first to propose a theorization of the farmer innovation tracking approaches, thus enriching the agronomic foundations supporting farming system design. The purpose of our paper is not to provide a turnkey method, but to highlight concepts, mechanisms, and points of reference for actors who might wish to develop farmer innovation tracking in different contexts in the future. By revealing their contributions to design processes, this article seeks to contribute to the institutionalization of innovation tracking.

Summary 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, Sezary 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 Sezary 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 Sezary 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 Sezary 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 Sezary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2. Funding Innate Pharma

Mitotic kinesins are essential regulators of cancer cell replication and migration. The microtubule associated motor protein KIF20A (also called MKlp2), a member of the kinesin-6 family, plays an essential role during cytokinesis and is also involved in the fission of RAB6-positive vesicles from Golgi membrane, therefore contributing to intracellular vesicular trafficking (1). KIF20A plays a critical role in the development and progression of many cancers, and its high expression is associated with disease progression and poor survival outcome (2). More specifically, immature hematopoietic cells, exhibit high KIF20A expression, whereas mature peripheral blood cells do not (3). Herein we describe the preclinical anti-leukemic efficacy of DIACC2010, sole-in-class selective KIF20A inhibitor. DIACC2010 demonstrated potent and consistent cytotoxic activity in-vitro against a panel of 9 human AML cell lines, with median IC50 of 40 nM (range 10-77 nM). In the same experimental conditions, cytarabine (CYTA) had median IC50 of 207 nM (range 4-1580 nM). In parallel, no in-vitro toxicity of DIACC2010 was observed on human normal cells such as peripheral blood mononuclear cells (PBMC) and primary hepatocytes (IC50 >50 µM). DIACC2010 was subsequently evaluated in-vivo in xenograft models of CYTA-sensitive and CYTA-resistant AML cell lines: DIACC2010 significantly improved overall survival as compared to CYTA in all models, with dose-dependent efficacy. On a mechanistic standpoint, DIACC2010-exposed AML cells displayed characteristic Golgi scattering leading to cell death, as hallmarks of DIACC2010 mode of action and target engagement. Altogether, these results confirm the relevance of KIF20A-directed therapeutic approaches and support the development of DIACC2010 for the treatment of AML. (1) Coupling fission and exit of RAB6 vesicles at Golgi hotspots though kinesin-myosin interactions, S. Miserey-Lenkei et al, Nature com, 2017, 104:300 (2) Prognostic significance of KIF2A and KIF20A expression in human cancer. X. Li et al, Medicine, 2019, 98:46 (3) KIF20A, highly expressed in immature hematopoietic cells, supports the growth of HL60 cell line, H. Morita et al, Int J Immunol, 2018,108:607 Citation Format: Yves COLLETTE, Rémy CASTELLANO, Michel AURRAND-LIONS, Hélène SICARD, Norbert VEY, Cécile BOUGERET. DIACC2010, a selective inhibitor of KIF20A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1813.

Sezary syndrome (SS) is a rare, aggressive leukemic form of cutaneous T-cell lymphoma characterized by generalized erythroderma, lymphadenopathy and circulating malignant CD4+ T cells (Sezary cells). Sezary syndrome evolves very quickly, patients are severely immunocompromised and their quality of life is drastically impaired. SS prognosis remains dismal despite recent therapeutic advances. AAC-11 (Anti-Apoptosis Clone 11, also known as Api5) is a survival scaffold protein that is widely expressed in cancer cells. Recent data indicate that AAC-11 might to be one of the central molecules involved in cancer cell progression and survival. Therefore, its inactivation might constitute an attractive approach for developing novel cancer therapeutics. AAC-11 contains a heptad leucine repeat domain that constitutes a protein-protein interaction motif, allowing its interaction with several apoptosis regulatory proteins. Loss-of-function mutations of the heptad leucine repeat motif are responsible for a defect in the interaction with its binding partners and associated with an abolition of the survival properties of AAC-11. We have recently described cell penetrating peptides based on the fusion of penetratin and a portion of the heptad leucine repeat region of AAC-11 that can induce cancer cells death. This effect is not observed in normal cells, suggesting high therapeutic indices. Here we evaluated the anti-tumor effect of a novel AAC-11-derived peptide, termed RT39, in the context of Sezary syndrome. Our results demonstrate that RT39 exerts an efficient and specific cytotoxic activity towards Sezary cells, while sparring the other immune cell populations, both ex vivo on primary patient cells and in vivo in preclinical Sezary syndrome murine models. Mechanistic studies revealed that RT39 induces membranolysis of Sezary cells by means of binding to p21-activated kinase 1 (PAK1) in the context of Sezary cells plasma membrane, where PAK1 is overexpressed. Preliminary pharmacokinetic studies in mice indicated that, after intravenous, subcutaneous or intraperitoneal administration, the half-life of the peptide is of the order of 30 minutes, but the elimination phase is very prolonged with high AUCs, indicative of durable exposure. Along with excellent tolerability in mice, our preclinical results support the development of RT39 as a new therapeutic strategy in Sezary syndrome.

Purpose: KIR3DL2 is a recently discovered marker of the malignant clonal cell population in Sézary syndrome. We intended to evaluate the expression of KIR3DL2 on blood T cells as a diagnostic, prognostic, and follow-up marker of Sézary syndrome. Experimental Design: Sixty-four patients diagnosed with Sézary syndrome were included in this monocentric study. We collected the percentage of KIR3DL2+ cells among CD3+ T cells, obtained by flow cytometry, and other classical diagnostic criteria for Sézary syndrome at diagnosis and during the follow-up. Results: Compared with the classical diagnostic factors, KIR3DL2 was the most sensitive diagnostic factor for Sézary syndrome. Univariate and multivariate analyses established that an eosinophil cell count >700/mm3 and a percentage of KIR3DL2+ cells within the CD3+ T cells >85% at diagnosis were associated with a significantly reduced disease-specific survival. Moreover, KIR3DL2 immunostaining allowed the assessment of treatment efficiency and specificity toward tumor cells, the detection of the residual disease following treatment, and the occurrence of relapse, even though patients clinically experienced complete remission and/or undetectable circulating Sézary cells by cytomorphologic analysis. Conclusions: We show that KIR3DL2 expression is the most sensitive diagnostic criterion of Sézary syndrome when compared with all other available biological criteria. It also represents the best independent prognostic factor for Sézary syndrome–specific death and the most relevant feature for the follow-up of Sézary syndrome, showing the invasion of the functional lymphocytes pool by Sézary cells. KIR3DL2 therefore represents a valuable tool for routine use as a clinical parameter at diagnosis, for prognosis and during patient follow-up. Clin Cancer Res; 23(14); 3619–27. ©2017 AACR.

Background KIR3DL2, an inhibitory receptor expressed by natural killer cells and a subset of normal CD8(+) T cells, is aberrantly expressed in neoplastic cells in transformed mycosis fungoides and Sezary syndrome. Anti-KIR3DL2 targeted antibody therapy has shown potent activity in preclinical models for these diseases. Objectives To examine the expression of KIR3DL2 and its potential use as a therapeutic target in patients with primary cutaneous anaplastic large-cell lymphoma (pcALCL), the most aggressive cutaneous CD30(+) lymphoproliferative disease. Methods Samples from 11 patients with pcALCL and three CD30(+) lymphoproliferative disease cell lines - Mac1, Mac2a and Mac2b - were used in KIR3DL2 expression studies using immunohistochemistry, flow cytometry and reverse-transcriptase quantitative polymerase chain reaction. The effect of IPH4102, a monoclonal humanized IgG1 targeting KIR3DL2, was assessed by in vitro cytotoxicity assays against Mac1, Mac2a and Mac2b using allogeneic peripheral blood mononuclear cells as effectors. Results KIR3DL2 mRNA and protein were found in all human samples of pcALCL, and in the Mac2a and Mac2b cell lines. KIR3DL2 protein expression was present on 85·8 ± 14·0% of CD30(+) skin-infiltrating tumour cells. In vitro functional studies showed that KIR3DL2(+) Mac2a and Mac2b pcALCL lines are sensitive to antibody-derived cytotoxicity mediated by IPH4102, through activation of natural killer cells, in a concentration-dependent manner. Conclusions pcALCL tumour cells express KIR3DL2, and we provide preclinical proof of concept for the use of IPH4102, a humanized anti-KIR3DL2 antibody, to treat patients with primary cutaneous CD30(+) ALCL.

International audience; No abstract available

Introduction KIR3DL2 est un recepteur NK exprime par 85 % des lymphomes T cutanes (LTC). IPH4102 est un anticorps (Ac) monoclonal « first-in-class » anti-KIR3DL2 qui deplete les cellules par des mecanismes d’ADCC et d’ADCP (cytotoxicite et phagocytose dependantes de l’anticorps). Il a ete teste pour la premiere fois chez l’homme dans une etude de phase I afin d’evaluer sa tolerance et de determiner la dose maximale toleree (DMT) et la dose recommandee pour une etude de phase 2 (RP2D). Les objectifs secondaires comportaient des etudes pharmacocinetiques et l’evaluation de l’efficacite clinique et biologique. Patients et methodes Les malades inclus etaient des LTC de stade avance refractaires a au moins 2 lignes de traitement systemique, dont les cellules tumorales exprimaient KIR3DL2 dans la peau et/ou le sang. L’escalade de dose comportait dix niveaux (0,0001 a 10 mg/kg). L’Ac etait administre par voie IV toutes les semaines pendant 4 semaines, toutes les 2 semaines jusqu’a la semaine 26 puis toutes les 4 semaines. Les malades pouvaient recevoir des doses croissantes et etaient traites jusqu’a progression ou survenue d’une toxicite. L’efficacite clinique etait evaluee selon les criteres internationaux. Les lymphocytes KIR3DL2 etaient monitores dans la peau par immunohistochimie et dans le sang par cytometrie de flux. La maladie residuelle etait evaluee par « deep sequencing » du recepteur T pour l’antigene. Resultats Vingt-cinq patients ont ete inclus : 20 syndromes de Sezary (SS), 4 mycosis fongoides (MF) et un LTC CD4+ NOS. L’âge median etait de 71 ans (42–90) et le nombre median de traitements precedents de 4 (2–14). Dix-neuf malades ont recu des doses croissantes d’Ac. Aucune toxicite limitante n’a ete observee et la DMT n’a pas ete atteinte. Six patients ont presente des evenements indesirables (EI) de grade 3, dont 2 lies au traitement et 2 des EI de grade 4 non lies au traitement. Les EI etaient pour la majorite des evenements de bas grade frequents lors de perfusions d’Ac. Le taux de reponses globales etait de 50 % pour les SS, dont 65 % de reponses dans le sang incluant 25 % de reponses completes. Les scores de prurit etaient tres ameliores chez tous les malades repondeurs et stables. Les lymphocytes KIR3DL2 ont ete progressivement et durablement depletes dans la peau et le sang. L’evaluation de la maladie residuelle a montre la disparition totale et durable du clone tumoral dans le sang et la peau. Une posologie de 10 mg/kg a ete choisie pour la phase d’extension. Conclusion Ces resultats montrent une excellente tolerance et une efficacite clinique tres prometteuse d’IPH4102 chez des malades ayant un LTC refractaire a plusieurs traitements systemiques. Une phase d’expansion de 15 malades ayant un syndrome de Sezary est en cours, les malades recevant une « flat dose » de 750 mg.

To the editor: KIR3DL2, a killer immunoglobulin-like receptor normally expressed by a subset of natural killer (NK) cells, is aberrantly expressed in Sezary syndrome (SS), an aggressive cutaneous T-cell lymphoma (CTCL). In SS patients, the detection of KIR3DL2 expression on circulating tumor cells

Sezary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sezary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+ T cells, CD164+ and CD164-CD4+ T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sezary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164-CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sezary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.

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. Cancer Res; 74(21); 6060–70. ©2014 AACR.

CD160 is a GPI-anchored Ig-like receptor identified by the BY55 mAb on human circulating CD56dim+ NK cells and TCRγδ lymphocytes. In addition, while most intestinal T lymphocytes express it, only a minor circulating CD4+ or CD8+ T lymphocyte subset is CD160+. Here we describe a population of CD4+CD160+ human blood T lymphocytes of circulating cutaneous T cells. These rare T lymphocytes represent 2.1 ± 1.9% of the circulating CD3+CD4+ T cells, coexpress CD8αα, CD244, and perforin but lack CD28 expression, a phenotype corresponding to effector memory cytotoxic T-lymphocytes. Functional studies further confirmed their cytotoxic potential. These cells lack αEβ7 integrin and CCR7 expression but do express skin-addressing molecules CLA, and CCR4. In normal human skin, CD4+CD160+ cells represent 34.6 ± 14.7% of the CD4+ T lymphocytes extracted by collagenase treatment. These T cells coexpress CLA (81 ± 13.6%), CCR4 (62.3 ± 15.9%), and some CD8αα (19.6 ± 13%) or CCR7 (24.4 ± 11.7%) expression. Cutaneous T-cell lymphoma cells express the natural killer receptor KIR3DL2 (CD158k) used as a tumor marker. Not only we confirmed the expression of this marker in the blood and/or skin of mycosis fungoides patients but we also show for the first time CD158k expression (often associated with CD160) on cutaneous CD4+ T cells from healthy individuals (25.3 ± 15%). Therefore, CD4+CD160+ T cells expressing CD158k might represent specialized cutaneous lymphocytes devoted to immune surveillance, from which could originate cutaneous T-cell lymphomas such as mycosis fungoides. © 2014 International Society for Advancement of Cytometry

International audience; During the last several years, research has produced a significant amount of knowledge concerning the characteristics of human γδ T lymphocytes. Findings regarding the immune functions of these cells, particularly their natural killer cell-like lytic activity against tumor cells, have raised expectations for the therapeutic applications of these cells for cancer. Pharmaceutical companies have produced selective agonists for these lymphocytes, and several teams have launched clinical trials of γδ T cell-based cancer therapies. The findings from these studies include hematological malignancies (follicular lymphoma, multiple myeloma, acute and chronic myeloid leukemia), as well as solid tumors (renal cell, breast and prostate carcinomas), consisting of samples from more than 250 patients from Europe, Japan and the United States. The results of these pioneering studies are now available, and this short review summarizes the lessons learned and the role of γδ T cell-based strategies in the current landscape of cancer immunotherapies.

Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin–restricted mycosis fungoides. Early diagnosis of SS is therefore key to achieving enhanced therapeutic responses. However, the lack of a biomarker (s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sézary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+T cells, CD164+ and CD164− CD4+ T cells isolated from patients with high circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sézary signature genes: T plastin, GATA-3, along with FCRL3, Tox and miR -214 was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164−CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sézary signature genes, FCRL3 and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.

Cet article étudie selon une approche alternative l’histoire culturelle du papier dans l’Europe occidentale moderne, en remettant en perspective les interactions entre papier imprimé et papier non imprimé. On y trouve une critique de la formule diachronique de Marshall McLuhan : « du manuscrit à l’imprimé ». McLuhan soutient que l’invention de l’imprimerie a conduit à une transformation historique brutale : le papier non imprimé n’a plus servi qu’à nourrir la production de papier imprimé, tandis que le statut moderne de l’auteur s’est trouvé irrévocablement rattaché à la nouvelle matérialisation de l’innovation et de l’autorité : le caractère d’imprimerie. Cet article préfère mettre l’accent sur les différentes strates dans l’usage du papier, telles qu’on les découvre dans les pratiques culturelles de la première modernité européenne (on peut penser au papier comme médium visuel), et plaide pour une réinterprétation de l’impact produit par l’imprimerie. Imprimé et non-imprimé ont été considérés à égalité et sont restés inséparables, car ils étaient chacun l’effet de la demande croissante de papier dans tous les domaines de la vie publique et privée. Pour montrer les effets culturels de cette tension entre papier imprimé et non imprimé, l’article propose une analyse de la fiction de l’éditeur. On sait que dans certains textes poétiques, le produit imprimé se réfère à sa propre histoire, en remontant à un manuscrit sur papier non imprimé., This article investigates an alternative approach to a cultural history of paper in modern Western Europe by reframing the interwoven relationship between the unprinted and the printed modes of paper. It hints at the limitations of Marshall McLuhan’s diachronic formula “from manuscript to print,” which contains the notion that the invention of the printing press led to a sudden historical shift where unprinted paper was reduced to serve as fuel for the production of printed paper, while the idea of modern authorship was irrevocably linked to the printed letter as the new material of innovation and authority. Rather, the article emphasizes the multi-layered uses of paper in cultural practices in early modern Europe (for instance, as a visual medium) and argues for a reinterpretation of the impact of the printing press. Here, the unprinted and the printed gained equal importance and remained intertwined as two effects of a growing demand for paper in various domains of public and private life. As an example of the cultural effects of the tension between printed and unprinted paper, the article analyzes the fiction of the publisher in poetic texts, in which the printed product refers to its own development as a result of unprinted manuscript on paper.

Cet article traite du « rythme », une notion abondamment discutée lors de l’émergence d’une littérature académique en histoire de l’art. Malgré l’utilisation qu’en faisaient déjà Karl Schnaase et Franz Kugler, ce n’est qu’après 1900 que le terme deviendra un principe de base sous l’influence d’August Schmarsow, à Leipzig, et d’Alois Riegl, à Vienne. Ces derniers reconnaissaient l’importance et le potentiel d’une telle notion, malgré leurs travaux divergents. Pour August Schmarsow, le rythme était le moyen de concevoir la relation de l’esthétique et de l’expérience physique : traverser une architecture, un mouvement rythmique donc, décrivait un mode de perception élémentaire. En revanche, pour Riegl, le rythme était une question de vision : en explorant l’esthétique de l’Antiquité tardive (qui anticipait, selon lui, le modernisme), il observait davantage le rythme dans les rapports dynamiques entre le blanc et le noir, une idée qui deviendra pertinente pour la théorie cinématographique des années 1920., The article is about the term “rhythm,” which was vividly discussed in the early days of academic art history writing. Although already used by scholars like Karl Schnaase and Franz Kugler, rhythm only became a basic principle after 1900. It was mainly August Schmarsow in Leipzig and Alois Riegl in Vienna who stressed the importance of that term. Both of them realized its innovative potential, but for different reasons. For Schmarsow rhythm was a means to link aesthetics with physical experience: walking through the architecture, thus a rhythmical movement, was described as a basic mode of perception. Riegl’s ideas about rhythm were quite different. For him rhythm was primarily a matter of seeing. Exploring the aesthetics of late antiquity (which Riegl understood as an anticipation of modernity) he focused on the rhythmic interrelation between black and white—an idea which became most relevant in the film-theory of the 1920s.

Aims: Sezary Syndrome (SS) is the most aggressive form of cutaneous T cell lymphoma (CTCL), characterized with high blood involvement and expression of Killer cell immunoglobulin like receptor 3DL2 (KIR3DL2). IPH4102 is a first-in-class monoclonal antibody that targets KIR3DL2. Very limited effective treatment options are available for SS patients with refractory disease. We conducted a phase 1 study testing IPH4102 in patients with refractory CTCL. Here we report results from the SS subset. Methods: IPH4102-101 study is a multicenter phase I trial composed of a dose escalation and cohort expansion portions that evaluated IPH4102 in patients with refractory CTCL. Key eligibility criteria included failure of ≥ 2 prior systemic therapies. KIR3DL2 testing was performed for all patients at baseline and at different time points throughout the study. IPH4102 was given Q1w x 4 weeks, followed by Q2w x 10 weeks then Q4w until disease progression or unacceptable toxicity. Primary endpoint is safety. Main 2ry endpoints include best global response (BGR) using the Olsen criteria, progression-free survival (PFS), duration of response (DOR), quality of life (QOL) and biomarker analyses. Results: The study included 35 SS patients, 20 in the dose escalation and 15 in the cohort expansion, with a median age of 70 years (37-90). Median time from initial SS diagnosis to starting IPH4012 was 22.8 months. Nineteen patients (54%) received IPH4102 as ≥ 4th line of systemic therapy and 7 (20%) were previously treated with mogamulizumab. Thirteen patients (37%) had lymph node involvement as per investigator assessment and based on radiological examination while 7 patients (20%) had evidence of large cell transformation. KIR3DL2 expression was observed in either skin or blood in 33 patients (94%) and in both in 28 patients (80%). Most common adverse events (AEs) were asthenia (26%), peripheral edema (26%), and fatigue (23%), which were all grade 1-2. Possibly related grade ≥ 3 AEs were observed in 7 patients (20%), and only 2 patients (6%) stopped treatment for an AE. Table 1 shows BGR and response by compartment. Overall response rate was 42.9% [95% CI: 28.0% - 59.1%], with median time to response of 4.8 months. Median DOR and PFS were 5.6 months [95% CI: 3.2-not reached] and 12.8 months [95% CI: 8.1-not reached], respectively. Mogamulizumab pretreated patients showed BGR, median DOR and PFS of 42.9%, 13.8 and 20.9 months, respectively. Quality of life assessment was performed using the Pruritus VAS score andSkinDex29. Patients with CR, PR or SD showed marked improvement overtime of all evaluated parameters including SkinDex29 global, symptoms, emotional, and functional scores. Biomarker analysis showed progressive decrease in CD4/CD8 ratio in responding patients. The decrease of KIR3DL2+ expressing cells in skin evaluated by immunohistochemistry at week 5 and 14 was able to predict BGR (AUC=0.749, 0.714, respectively). Figure 1 shows reduction in KIR3DL2 expressing cells at week 5 and week 14 in a patient who had PR as BGR. To date, 9 patients are still ongoing treatment. Updated clinical and correlative research analyses will be presented at the meeting. Conclusions: IPH4102 is highly effective in patients with refractory SS. It induces meaningful clinical activity and improves quality of life placing it as an encouraging treatment option for these patients. Further development in SS and other T-cell malignancies is underway. Disclosures Bagot: Actelion: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Porcu:Innate Pharma: Consultancy. Khodadoust:Innate Pharma: Research Funding. Sicard:Innate Pharma: Employment, Equity Ownership. Azim:Innate Pharma: Employment, Equity Ownership. Kim:miRagen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Galderma: Research Funding; Tetralogic: Research Funding; Neumedicine: Consultancy, Research Funding; Soligenix: Research Funding; Portola: Research Funding; Forty Seven Inc: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Vgamma9Vdelta2 (gammadelta) T lymphocytes, a critical peripheral blood lymphocyte subset, are directly cytotoxic against many solid and hematologic tumor types. Vgamma9Vdelta2 T lymphocytes can be selectively expanded in vivo with BrHPP (IPH1101) and IL-2. The present phase I trial was conducted with the aim of determining the maximum-tolerated dose (MTD) and safety of IPH1101 combined with a low dose of IL-2 in patients with solid tumors.A 1-h intravenous infusion of IPH11 was administered alone at cycle 1, combined with a low dose of SC IL-2 (1 MIU/M(2) d1 to d7) in the subsequent cycles (day 1 every 3 weeks). The dose of IPH1101 was escalated from 200 to 1,800 mg/m(2).As much as 28 patients with solid tumors underwent a total of 109 treatment cycles. Pharmacodynamics data demonstrate that gammadelta T lymphocyte amplification in humans requires the co-administration of IL-2 and is dependent on IPH 1101 dose. Dose-limiting toxicity occurred in two patients at a dose of 1,800 mg/m(2): one grade 3 fever (1 patient) and one grade 3 hypotension (1 patient) suggesting cytokine release syndrome immediately following the first infusion. At lower doses the treatment was well tolerated; the most frequent adverse events were mild fever, chills and abdominal pain, without exacerbation in the IL-2 combined cycles.IPH1101 in combination with SC low-dose IL-2 is safe, well tolerated and induces a potent gammadelta T lymphocyte expansion in patients. Its clinical activity will be evaluated in phase II clinical trials.

gammadelta T lymphocytes are attractive effector cells for immunotherapy. In vitro, they can be expanded and kill efficiently a variety of tumor cells. The frequency and distribution of gammadelta T lymphocytes were compared in tumor lymph nodes of 51 patients with follicular lymphoma lymph nodes (FL-LNs) and 28 patients with inflammatory lymph nodes (I-LNs). gammadelta and CD8 T lymphocytes were less abundant in FL-LNs than in I-LNs (p

Interest in gamma9delta2 T cells has increased greatly in the past decade. While several protocols allowed the amplification of a large proportion of these cells in vitro, the purity of the final preparation is usually heterogeneous between different donors. Functional studies of this population are often controversial due to the presence of other populations such as NK cells which share a wide range of characteristics. Here, the gamma9delta2 T cells labelled-fraction is purified and mixed with the irradiated unlabelled fraction followed by a single stimulation with phosphoantigen, in turn followed by a classical step of amplification in the presence of interleukin 2. In this study, we describe a straightforward protocol to amplify pure populations of gamma9delta2 T cells which could be useful in fundamental research or in the development of a new generation of gammadelta cell therapy protocol.

When Francoise de Graffigny's epistolary novel Lettres d'une Peruvienne appeared in 1747, one of her close friends, the French economist Jacques Turgot, praised the native of the region of Lorraine for crafting a subtle philosophical work capable of regenerating, if not revolutionizing, the genre of the novel itself. As Janet Altman points out in her article "A Woman in The Enlightenment Sun," Turgot's enthusiastic reception was subsequently taken up not only in the Enlightenment Encyclopedie--where several entries were devoted to Graffigny's Peruvian heroine, the Inca Princess Zilia--but also in the portrait gallery assembled by D'Agoty in 1770, in which Graffigny figured as "the deceased writer most capable of representing the Enlightenment ideals" (Altman 269). For Graffigny's contemporaries, the writer's innovative contribution to French literature resided primarily in the singular novelistic heroine she had invented by combining two allegedly incompatible types of characters" the sentimental heroine and the cultural critic of oriental fictions. Over the past two decades, the Lettres d'une Peruvienne bave once again received increased critical attention. Like their predecessors, recent critics have also focused on the novel's heroine. But the question dominating more recent debates has tended to revolve around the authenticity, or rather lack thereof, of Graffigny's representation of Peruvian culture. (1) Graffigny's deviations from typical eighteenth-century representations of Peruvian realities have generally been attributed to her supposed naivety or lack of familiarity with Peru, if not her insufficient mastery of literary conventions. However, like many writers of oriental fictions, Graffigny was not necessarily concerned with providing her readership with an ethnographic account of the non-European culture she represents in her novel, i.e. Inca civilization. The preface of the Lettres d'une Peruvienne indeed suggests that the writer did not intend to craft her heroine according to received notions of Inca civilization; on the contrary, Graffigny seems precisely to call into question such notions: Si la verite, qui s'ecarte du vraisemblable, perd ordinairement son credit aux yeux de la raison, ce n'est pas sans retour; mais pour peu qu'elle contrarie le prejuge, rarement elle trouve grace devant son tribunal. Que ne doit donc pas craindre l'editeur de cet ouvrage, en presentant au public les lettres d'une jeune Peruvienne, dont le style et les pensees ont si peu de rapport avec l'idee mediocrement avantageuse qu'un injuste prejuge nous a fait prendre de sa nation [...] Nous meprisons les Indiens; a peine accordons-nous une ame pensante a ces peuples malheureux. (249) As this passage makes clear, Graffigny consciously undermines stereotypical representations of Inca cultural identity, foregrounding Zilia's singular subjectivity instead by emphasizing her cultural agency (her literary "style") and intellectual qualities (her "thoughts"), as opposed to an alleged Peruvian naivety. The gaps between conventional representations of Inca culture and Graffigny's own, which critics have not failed to notice, thus appear to "unmark" the heroine from her supposed Peruvianness rather than indicating any failing on the writer's part. Consequently, such a displacement of Zilia's "Peruvian" identity problematizes the literal reading of the character. Departing from the ethnographic approach of recent secondary literature, I wish to suggest an alternative reading of Graffigny's Inca Princess as a fictional double for the writer herself. As Janet Altman bas argued, the story of Zilia's exile and of the conquest of Peru certainly provides a forum for a critique of European imperialism in the third world. (2) But it also allowed Graffigny to work through the effects of French imperialism more close to home: namely within her native Lorraine. Previously an independent duchy, Lorraine became a French protectorate at the end of the war of the succession of Poland in 1738. …

Although Foxp3(+) T regulatory cells (Tregs) are well documented for their ability to suppress various immune cells, T-cell subsets capable of counteracting Tregs have not been demonstrated. Here, we assessed phosphoantigen-activated Vgamma2Vdelta2 T cells for the ability to interplay with Tregs in the context of mycobacterial infection. A short-term IL-2 treatment regimen induced marked expansion of CD4(+)CD25(+)Foxp3(+) T cells and subsequent suppression of mycobacterium-driven increases in numbers of Vgamma2Vdelta2 T cells. Surprisingly, activation of Vgamma2Vdelta2 T cells by adding phosphoantigen Picostim to the IL-2 treatment regimen down-regulated IL-2-induced expansion of CD4(+)CD25(+)Foxp3(+) T cells. Consistently, in vitro activation of Vgamma2Vdelta2 T cells by phosphoantigen plus IL-2 down-regulated IL-2-induced expansion of CD4(+)CD25(+)Foxp3(+) T cells. Interestingly, anti-IFN-gamma-neutralizing antibody, not anti-TGF-beta or anti-IL-4, reduced the ability of activated Vgamma2Vdelta2 T cells to down-regulate Tregs, suggesting that autocrine IFN-gamma and its network contributed to Vgamma2Vdelta2 T cells' antagonizing effects. Furthermore, activation of Vgamma2Vdelta2 T cells by Picostim plus IL-2 treatment appeared to reverse Treg-driven suppression of immune responses of phosphoantigen-specific IFNgamma(+) or perforin(+) Vgamma2Vdelta2 T cells and PPD-specific IFNgamma(+)alphabeta T cells. Thus, phos-phoantigen activation of Vgamma2Vdelta2 T cells antagonizes IL-2-induced expansion of Tregs and subsequent suppression of Ag-specific antimicrobial T-cell responses in mycobacterial infection.

Gammadelta-T-lymphocytes contribute to innate immunity and are selectively activated by nonpeptide phosphorylated molecules (so-called phosphoantigens) produced by organisms responsible for causing a broad range of infectious diseases. gammadelta-T-cells are also activated by synthetic phosphoantigens and are cytotoxic to tumor cells. Here we report the synthesis, NMR characterization, and comparative biological evaluation of new pyrophosphate, phosphonate, and pyrophosphonate monoesters whose structures correspond to isosteric analogues and stereoisomers of the highly potent isoprenoid metabolite ( E)-1-hydroxy-2-methylbut-2-enyl 4-diphosphate called HDMAPP (hydroxy-dimethyl-allyl pyrophosphate). Both pyrophosphate and pyrophosphonate series elicit promising gammadelta-T-cell stimulatory responses in vitro, the pyrophosphonate ester (C-HDMAPP) being by far more stable than its parent pyrophosphate ester (HDMAPP) with improved ADMET properties and a similar pharmacodynamic profile based on in vivo studies in nonhuman primate. In both series, we found that E-stereoisomers are the most active derivatives and that Z-stereoisomers show very marginal bioactivity levels. These results indicate that the use of bioisosteric analogues of HDMAPP may represent promising new leads for immunotherapy.

Drawing on the ideas developed by Judith Butler in her book Bodies That Matter , this article interprets Virginie Despentes' first novel Baise-moi as a literary reflection on the violent implications of the constitution and preservation of a coherent female subjectivity. The first part of the article examines the highly complex relationship that develops between Despentes' heroines over the course of the novel, showing that the two female protagonists cannot be reduced to a single subjectivity. Building on this analysis, the second part then highlights two principles of Despentes' feminism: her refusal of analogical thinking and her affirmation of contradictory identities.

Contemporary critics of Charles Baudelaire's 1863 prose poem "La Belle Dorothee" have interpreted the figure of the liberated female slave Dorothee as a slave of imitation of whiteness. Drawing on colonial history, postcolonial theory, as well as recent developments in Baudelairean criticism, this article focuses on the poem's formal features to argue for a reading of Dorothee as a successful embodiment of emancipation without cultural assimilation. (In French)

Cet article se consacre à une dimension virtuelle de l’art des archives liée aux processus mémoriels et perceptifs propres à l’expérience des films. Ainsi, chez l’artiste viennoise Constanze Ruhm s’avère une approche moderniste des « archives » du film, se nourrissant à la fois de l’art conceptuel et de la théorie du cinéma. Le dispositif des films « premiers » sera compris, dans cette élaboration secondaire, comme espace structurant du regard et comme relais par rapport aux formes narratives spécifiques. L’artiste conçoit dans des environnements, dans des animations numériques ou encore dans des films et installations multimédias, des reconfigurations et des réincarnations (« re-enactments ») de scènes de l’histoire du cinéma moderne. La création de nouvelles sections et connexions ouvre dans cette oeuvre des formes variées de virtualité qui ne visent pas une position fixe du spectateur, mais des modes actifs d’observation. Par la multiplication des histoire(s) dans un cut-up de scénarios, la possibilité de former des espaces narratifs homogènes s’abolit. C’est par le mode de répétition et d’actualisation du passé que chez Ruhm une image du virtuel se dessine, en tant que série de déplis et de projections. Ainsi, on cerne le virtuel comme quelque chose qui se forme au cours de processualités interminables, au-delà de stéréotypes narratifs, chaque fois différemment., This article looks at a virtual dimension of the archive as an artform linked to the memorial and perceptual processes specific to the experience of film, and takes as its subject the work of Viennese artist Constanze Ruhm, which evinces a modernist approach to film “archives,” informed by both conceptual art and film theory. The apparatus of the “primary” films here comes to be understood, through Ruhm’s secondary elaboration, as a space that structures the viewer’s gaze, and as a relay in relation to specific narrative forms. Recontextualized through curated environments, digital animations, and multimedia films and installations, the artist conceives of reconfigurations and reenactments of scenes from the history of modern cinema. The creation of new components and connections in this work introduces various forms of virtuality that are not directed towards the fixed position of the viewer, but instead towards more active modes of observation. The multiplication of storylines created by the cut-up technique abolishes the possibility of homogeneous narrative space. Through Ruhm’s use of repetition and reenacting the past, an image of the virtual emerges as a series of unfoldings and projections. In this way, we discover the virtual as something formed in the course of interminable processes, beyond the stereotypes of narrative, each time anew, but different.

CD160 is a GPI-anchored Ig-like receptor identified by the BY55 mAb on human circulating CD56dim+ NK cells and TCRγδ lymphocytes. In addition, while most intestinal T lymphocytes express it, only a minor circulating CD4+ or CD8+ T lymphocyte subset is CD160+. Here we describe a population of CD4+ CD160+ human blood T lymphocytes of circulating cutaneous T cells. These rare T lymphocytes represent 2.1 ± 1.9% of the circulating CD3+ CD4+ T cells, coexpress CD8αα, CD244, and perforin but lack CD28 expression, a phenotype corresponding to effector memory cytotoxic T-lymphocytes. Functional studies further confirmed their cytotoxic potential. These cells lack αEβ7 integrin and CCR7 expression but do express skin-addressing molecules CLA, and CCR4. In normal human skin, CD4+ CD160+ cells represent 34.6 ± 14.7% of the CD4+ T lymphocytes extracted by collagenase treatment. These T cells coexpress CLA (81 ± 13.6%), CCR4 (62.3 ± 15.9%), and some CD8αα (19.6 ± 13%) or CCR7 (24.4 ± 11.7%) expression. Cutaneous T-cell lymphoma cells express the natural killer receptor KIR3DL2 (CD158k) used as a tumor marker. Not only we confirmed the expression of this marker in the blood and/or skin of mycosis fungoides patients but we also show for the first time CD158k expression (often associated with CD160) on cutaneous CD4+ T cells from healthy individuals (25.3 ± 15%). Therefore, CD4+ CD160+ T cells expressing CD158k might represent specialized cutaneous lymphocytes devoted to immune surveillance, from which could originate cutaneous T-cell lymphomas such as mycosis fungoides.

Phosphoantigens (PAgs) activate Vγ9Vδ2 T lymphocytes, inducing their potent and rapid response in vitro and in vivo. However, humans and nonhuman primates that receive repeated injections of PAgs progressively lose their Vγ9Vδ2 T cell response to them. To elucidate the molecular mechanisms of this in vivo desensitization, we analyzed the transcriptome of circulating Vγ9Vδ2 T cells from macaques injected with PAg. We showed that three PAg injections induced the activation of the PPARα pathway in Vγ9Vδ2 T cells. Thus, we analyzed the in vitro response of Vγ9Vδ2 T cells stimulated with a PPARα agonist. We demonstrated that in vitro PPARα pathway activation led to the inhibition of the BrHPP-induced activation and proliferation of human Vγ9Vδ2 T cells. Since the PPARα pathway is involved in the antigen-selective desensitization of human Vγ9Vδ2 T cells, the use of PPARα inhibitors could enhance cancer immunotherapy based on Vγ9Vδ2 T cells.

Non-Hodgkin’s B lymphomas (NHL) are often resistant to conventional treatments and, until now, immunotherapeutic approaches against NHL only aimed at inducing αβ anti-tumor effectors. Nevertheless, human blood Vγ9Vδ2 T lymphocytes represent an abundant pool of cytotoxic tumor-reactive cells. Vγ9Vδ2 T cells are strongly activated by natural compounds, from which powerful synthetic ligands have been derived. These synthetic antigens induce efficient Vγ9Vδ2 T cell responses in vitro. We set up a series of Vγ9Vδ2 T cell-activation experiments, including cytotoxic activity and amplification from whole blood cells. Several types of Vγ9Vδ2 effectors were challenged against a panel of 16 B lymphoma cell lines. These tests have been performed in the absence and presence of γδ-specific synthetic ligands to evaluate the effect of such molecules on γδ anti-tumor activity. We report here that Vγ9Vδ2 T cells recognize B lymphomas. This recognition is associated with the cytotoxic activity against B-lymphoma cells and/or proliferative responses, and appears to be T-cell antigen receptor (TCR)-dependent. Because few B lymphoma induce a complete set of Vγ9Vδ2 cell responses, a chemical ligand of Vγ9Vδ2 T cells was used to enhance both proliferation and cytotoxic activity of anti-B lymphoma effectors. We show that such synthetic compound improves Vγ9Vδ2 CTL numbers and lysis of B lymphoma lines, especially when the targets are already spontaneously recognized by these effectors. We report here that human Vγ9Vδ2 T cells anti-B lymphoma response can be improved by use of specific synthetic ligands, which enhance their cytotoxic activity and allows their rapid expansion ex vivo.