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Jonathan Fisher, Pierre Abramowski, Nisansala Dilrukshi Wisidagamage Don, Barry Flutter, Anna Capsomidis, Gordon Weng-Kit Cheung, Kenth Gustafsson, John Anderson
Chimeric antigen receptors (CARs) combine T cell activation with antibody-mediated tumor antigen specificity, bypassing the need for T cell receptor (TCR) ligation. A limitation of CAR technology is on-target off-tumor toxicity caused by target antigen expression on normal cells. Using GD2 as a model cancer antigen, we hypothesized that this could be minimized by using T cells expressing Vγ9Vδ2 TCR, which recognizes transformed cells in a major histocompatibility complex (MHC)-unrestricted manner, in combination with a co-stimulatory CAR that would function independently of the TCR...
March 21, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
Biqing Han, Yanmin Zhao, Yu Lin, Shan Fu, Limengmeng Wang, Mingming Zhang, Ruxiu Tie, Binsheng Wang, Yi Luo, Lizhen Liu, Jian Yu, He Huang
Hydroxychloroquine (HCQ) is the only autophagy inhibitor in clinical use and it has shown great potential in treating chronic myeloid leukemia (CML). By inhibiting autophagy, HCQ enhances the anti-CML efficiency of chemotherapy. In the present study, we demonstrated that HCQ sensitized CML cells to Vγ9Vδ2 T cell-mediated lysis. HCQ inhibited autophagy in CML cells, but the sensitizing effects of HCQ were autophagy-independent. Since the sensitization was not mimicked by ATG7 knockdown and even occurred in the absence of ATG7...
March 24, 2017: International Journal of Oncology
Rebekah R Shippy, Xiaochen Lin, Sherry S Agabiti, Jin Li, Brendan M Zangari, Benjamin J Foust, Michael M Poe, Chia-Hung Christine Hsiao, Olga Vinogradova, David F Wiemer, Andrew J Wiemer
Butyrophilin 3A1 (BTN3A1) binds small phosphorus-containing molecules, which initiates transmembrane signaling and activates butyrophilin-responsive cells. We synthesized several phosphinophosphonates and their corresponding tris-pivaloyloxymethyl (tris-POM) prodrugs and examined their effects on BTN3A1. An analog of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) bound to BTN3A1 with intermediate affinity, which was enthalpy-driven. Docking studies revealed binding to the basic surface pocket and interactions between the allylic hydroxyl group and the BTN3A1 backbone...
March 1, 2017: Journal of Medicinal Chemistry
Karoline Fechter, Akaitz Dorronsoro, Emma Jakobsson, Izaskun Ferrin, Valérie Lang, Pilar Sepulveda, Daniel J Pennington, César Trigueros
γδ T cells play a role in a wide range of diseases such as autoimmunity and cancer. The majority of circulating human γδ T lymphocytes express a Vγ9Vδ2+ (Vδ2+) T cell receptor (TCR) and following activation release pro-inflammatory cytokines. In this study, we show that IFNγ, produced by Vδ2+ cells, activates mesenchymal stem cell (MSC)-mediated immunosupression, which in turn exerts a negative feedback mechanism on γδ T cell function ranging from cytokine production to proliferation. Importantly, this modulatory effect is limited to a short period of time (<24 hours) post-T cell activation, after which MSCs can no longer exert their immunoregulatory capacity...
2017: PloS One
Renée C G de Bruin, Anita G M Stam, Anna Vangone, Paul M P van Bergen En Henegouwen, Henk M W Verheul, Zsolt Sebestyén, Jürgen Kuball, Alexandre M J J Bonvin, Tanja D de Gruijl, Hans J van der Vliet
Vγ9Vδ2 T cell activation plays an important role in antitumor and antimicrobial immune responses. However, there are conditions in which Vγ9Vδ2 T cell activation can be considered inappropriate for the host. Patients treated with aminobisphosphonates for hypercalcemia or metastatic bone disease often present with a debilitating acute phase response as a result of Vγ9Vδ2 T cell activation. To date, no agents are available that can clinically inhibit Vγ9Vδ2 T cell activation. In this study, we describe the identification of a single domain Ab fragment directed to the TCR of Vγ9Vδ2 T cells with neutralizing properties...
January 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Aneta Zysk, Mark O DeNichilo, Vasilios Panagopoulos, Irene Zinonos, Vasilios Liapis, Shelley Hay, Wendy Ingman, Vladimir Ponomarev, Gerald Atkins, David Findlay, Andrew Zannettino, Andreas Evdokiou
Bone metastases occur in over 75% of patients with advanced breast cancer and are responsible for high levels of morbidity and mortality. In this study, ex vivo expanded cytotoxic Vγ9Vδ2 T cells isolated from human peripheral blood were tested for their anti-cancer efficacy in combination with zoledronic acid (ZOL), using a mouse model of osteolytic breast cancer. In vitro, expanded Vγ9Vδ2 T cells were cytotoxic against a panel of human breast cancer cell lines, and ZOL pre-treatment further sensitised breast cancer cells to killing by Vγ9Vδ2 T cells...
February 1, 2017: Cancer Letters
Audrey Benyamine, Aude Le Roy, Emilie Mamessier, Julie Gertner-Dardenne, Céline Castanier, Florence Orlanducci, Laurent Pouyet, Armelle Goubard, Yves Collette, Norbert Vey, Emmanuel Scotet, Remy Castellano, Daniel Olive
Given their recognized ability to kill acute myeloid leukemia (AML) blasts both in vitro and in vivo, Vγ9Vδ2 T cells are of growing interest in the design of new strategies of immunotherapy. We show that the Butyrophilin3A (BTN3A, CD277) subfamily is a critical determinant of Vγ9Vδ2 TCR-mediated recognition of human primary AML blasts ex vivo. Moreover, anti-BTN3A 20.1 agonist monoclonal antibodies (mAbs) can trigger BTN3A on AML blasts leading to further enhanced Vγ9Vδ2 T cell-mediated killing, but this mAb had no enhancing effect upon NK cell-mediated killing...
2016: Oncoimmunology
Joseph G Pressey, Julia Adams, Lualhati Harkins, David Kelly, Zhiying You, Lawrence S Lamb
INTRODUCTION: CD3+ γδ+ T cells comprise 2% to 5% of circulating T cells with Vγ9Vδ2+ cells the dominant circulating subtype. Vγ9Vδ2+ cells recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of γδ T cells represent a promising immunotherapeutic strategy for treatment of solid malignancies including neuroblastoma (NB). In this prospective, non-randomized Phase I trial, we assessed whether circulating Vγ9Vδ2+ cells could be safely expanded using intravenous ZOL (Zoledronate [Zometa]) and subcutaneous Interleukin-2 (IL-2) in patients with refractory NB...
September 2016: Medicine (Baltimore)
Patrik Theodor Nerdal, Christian Peters, Hans-Heinrich Oberg, Hristo Zlatev, Marcus Lettau, Elgar Susanne Quabius, Sofia Sousa, Daniel Gonnermann, Seppo Auriola, Daniel Olive, Jorma Määttä, Ottmar Janssen, Dieter Kabelitz
Human Vγ9Vδ2 T cells recognize in a butyrophilin 3A/CD277-dependent way microbial (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) or endogenous pyrophosphates (isopentenyl pyrophosphate [IPP]). Nitrogen-bisphosphonates such as zoledronic acid (ZOL) trigger selective γδ T cell activation because they stimulate IPP production in monocytes by inhibiting the mevalonate pathway downstream of IPP synthesis. We performed a comparative analysis of the capacity of purified monocytes, neutrophils, and CD4 T cells to serve as accessory cells for Vγ9Vδ2 T cell activation in response to three selective but mechanistically distinct stimuli (ZOL, HMBPP, agonistic anti-CD277 mAb)...
September 12, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Shou-Hui Du, Zhendong Li, Can Chen, Wee-Kiat Tan, Zhixia Chi, Timothy Weixin Kwang, Xue-Hu Xu, Shu Wang
Gamma delta (γδ) T cells and cytokine-induced killer (CIK) cells, which are a heterogeneous population of T lymphocytes and natural killer T (NKT) cells, have been separately expanded ex vivo and shown to be capable of targeting and mediating cytotoxicity against various tumor cells in a major histocompatibility complex-unrestricted manner. However, the co-expansion and co-administration of these immune cells have not been explored. In this study we describe an efficient method to expand simultaneously both CIK and Vγ9Vδ2 T cells, termed as CIKZ cells, from human peripheral blood mononuclear cells (PBMCs) using Zometa, interferon-gamma (IFN-γ), interleukin 2 (IL-2), anti-CD3 antibody and engineered K562 feeder cells expressing CD64, CD137L and CD86...
2016: PloS One
Elena Lo Presti, Nadia Caccamo, Valentina Orlando, Francesco Dieli, Serena Meraviglia
Vγ9Vδ2 T cells and plasmacytoid dendritic cells (pDCs) are two distinct cell types of innate immunity that participate in early phases of immune response. We investigated whether a close functional relationship exists between these two cell populations using an in vitro co-culture in a human system.pDCs that had been activated by IL-3 and the TLR9 ligand CpG induced substantial activation of Vγ9Vδ2 T cells upon co-culture, which was cell-to-cell contact dependent, as demonstrated in transwell experiments, but that did not involve any of the costimulatory molecules potentially expressed by pDCs or Vγ9V2 T cells, such as ICOS-L, OX40 and CD40L...
September 20, 2016: Oncotarget
Ieronymos Voskakis, Christina Tsekoura, Theodora Keramitsoglou, Evangelos Tsantoulas, Efthimios Deligeoroglou, George Creatsas, Marighoula Varla-Leftherioti
PROBLEM: Vγ9Vδ2 T cells (γ9δ2) are involved in antibacterial immune responses. The aim of this study was to look for associations between peripheral blood (PB) γ9δ2 T cells and cervix/vaginal Chlamydia trachomatis (Ct) infection in women with recurrent spontaneous abortions (RSA). METHOD OF STUDY: Peripheral blood samples were obtained from 201 RSA women within 10 days after they experienced a new miscarriage. γ9δ2 T cells and their percentage in total γδ T cells were compared between women who had been found and women who had not been found infected with Ct (last 6 months)...
November 2016: American Journal of Reproductive Immunology: AJRI
Ulrich Jarry, Cynthia Chauvin, Noémie Joalland, Alexandra Léger, Sandrine Minault, Myriam Robard, Marc Bonneville, Lisa Oliver, François M Vallette, Henri Vié, Claire Pecqueur, Emmanuel Scotet
Glioblastoma multiforme (GBM) represents the most frequent and deadliest primary brain tumor. Aggressive treatment still fails to eliminate deep brain infiltrative and highly resistant tumor cells. Human Vγ9Vδ2 T cells, the major peripheral blood γδ T cell subset, react against a wide array of tumor cells and represent attractive immune effector T cells for the design of antitumor therapies. This study aims at providing a preclinical rationale for immunotherapies in GBM based on stereotaxic administration of allogeneic human Vγ9Vδ2 T cells...
June 2016: Oncoimmunology
Laura Felley, Jenny E Gumperz
The central paradigm of conventional MHC-restricted T cells is that they respond specifically to foreign peptides, while displaying tolerance to self-antigens. In contrast, it is now becoming clear that a number of innate-like T cell subsets-CD1-restricted T cells, Vγ9Vδ2 T cells, and MAIT cells-may operate by different rules: rather than focusing on the recognition of specific foreign antigens, these T cells all appear to respond to alterations to lipid-related pathways. By monitoring perturbations to the "lipidome," these T cells may be able to spring into action to deal with physiological situations that are of self as well as microbial origin...
August 2016: Immunogenetics
Renée C G de Bruin, Sinéad M Lougheed, Liza van der Kruk, Anita G Stam, Erik Hooijberg, Rob C Roovers, Paul M P van Bergen En Henegouwen, Henk M W Verheul, Tanja D de Gruijl, Hans J van der Vliet
Vγ9Vδ2-T cells constitute the predominant subset of γδ-T cells in human peripheral blood and have been shown to play an important role in antimicrobial and antitumor immune responses. Several efforts have been initiated to exploit these cells for cancer immunotherapy, e.g. by using phosphoantigens, adoptive cell transfer, and by a bispecific monoclonal antibody based approach. Here, we report the generation of a novel set of Vγ9Vδ2-T cell specific VHH (or nanobody). VHH have several advantages compared to conventional antibodies related to their small size, stability, ease of generating multispecific molecules and low immunogenicity...
August 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Georg Gruenbacher, Hubert Gander, Andrea Rahm, Marco Idzko, Oliver Nussbaumer, Martin Thurnher
In humans, Vγ9Vδ2 T cells respond to self and pathogen-associated, diphosphate-containing isoprenoids, also known as phosphoantigens (pAgs). However, activation and homeostasis of Vγ9Vδ2 T cells remain incompletely understood. Here, we show that pAgs induced expression of the ecto-ATPase CD39, which, however, not only hydrolyzed ATP but also abrogated the γδ T cell receptor (TCR) agonistic activity of self and microbial pAgs (C5 to C15). Only mevalonate-derived geranylgeranyl diphosphate (GGPP, C20) resisted CD39-mediated hydrolysis and acted as a regulator of CD39 expression and activity...
July 12, 2016: Cell Reports
Ashley M Kilcollins, Jin Li, Chia-Hung Christine Hsiao, Andrew J Wiemer
Vγ9Vδ2 effector T cells lyse cells in response to phosphorus-containing small molecules, providing primates a unique route to remove infected or malignant cells. Yet, the triggering mechanisms remain ill defined. We examined lysis mediated by human Vγ9Vδ2 effector T cells in response to the naturally occurring (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) or a synthetic cell-permeable prodrug, bis (pivaloyloxymethyl) (E)-4-hydroxy-3-methyl-but-2-enyl phosphonate. CD27(+)/CD45RA(-) Th1-like effector cells killed K562 target cells through a mechanism that could be enhanced by either compound or TCR Ab and blocked by Src inhibition or butyrophilin 3 isoform A1 (BTN3A1) disruption...
July 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Zsolt Sebestyen, Wouter Scheper, Anna Vyborova, Siyi Gu, Zuzana Rychnavska, Marleen Schiffler, Astrid Cleven, Coraline Chéneau, Martje van Noorden, Cassie-Marie Peigné, Daniel Olive, Robert Jan Lebbink, Rimke Oostvogels, Tuna Mutis, Gerrit Jan Schuurhuis, Erin J Adams, Emmanuel Scotet, Jürgen Kuball
Human Vγ9Vδ2 T cells respond to tumor cells by sensing elevated levels of phosphorylated intermediates of the dysregulated mevalonate pathway, which is translated into activating signals by the ubiquitously expressed butyrophilin A1 (BTN3A1) through yet unknown mechanisms. Here, we developed an unbiased, genome-wide screening method that identified RhoB as a critical mediator of Vγ9Vδ2 TCR activation in tumor cells. Our results show that Vγ9Vδ2 TCR activation is modulated by the GTPase activity of RhoB and its redistribution to BTN3A1...
May 31, 2016: Cell Reports
Bhawna Poonia
AIM: Vγ9Vδ2 γδ T cells have effector potential against several cancers and infectious agents. Whether these cells control HIV replication was tested in humanized mouse model. METHODS: NOD SCID gamma mice engrafted with human peripheral blood mononuclear cells (PBMCs) and infected with HIVBAL were treated with zoledronate-expanded Vγ9Vδ2 T cells either alone or in combination with an anti-HIV envelope antibody b12. RESULTS: Severe depletion of CD4+CCR5+ T cells was observed in PBMCs of all infected mice...
May 2016: Immunotherapy
V Marcu-Malina, D Garelick, N Peshes-Yeloz, A Wohl, L Zach, M Nagar, N Amariglio, M J Besser, Z R Cohen, I Bank
The goal of this work was to assess the potential of T cells expressing Vγ9Vδ2+ T cell receptors (TCR, γ9δ2T cells) present in peripheral blood (PB) m ononuclear cells (MC, PBMC) of glioblastoma multiforme (GBM) patients to act as anti-tumoral agents. We found that γ9δ2T cell levels were decreased in patients' PB relative to a cohort of healthy donors (HD) (respectively 0.52±0.55%, n=16, vs 1.12±0.6%, n=14, p=0.008) but did not significantly correlate with postoperative survival (R=0.6, p=0.063). Importantly, however, the γ9δ2T cells could be expanded in vitro to consist 51±23% of the cultured lymphocytes (98% CD3+)...
January 2016: Journal of Biological Regulators and Homeostatic Agents
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