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Markus Granzin, Ana Stojanovic, Matthias Miller, Richard Childs, Volker Huppert, Adelheid Cerwenka
Natural killer (NK) cells are promising antitumor effector cells, but the generation of sufficient NK cell numbers for adoptive immunotherapy remains challenging. Therefore, we developed a method for highly efficient ex vivo expansion of human NK cells. Ex vivo expansion of NK cells in medium containing IL-2 and irradiated clinical-grade feeder cells (EBV-LCL) induced a 22-fold NK cell expansion after one week that was significantly increased to 53-fold by IL-21. Repeated stimulation with irradiated EBV-LCL and IL-2 and addition of IL-21 at the initiation of the culture allowed sustained NK cell proliferation with 10(11)-fold NK cell expansion after 6 weeks...
2016: Oncoimmunology
Hung C Tran, Zesheng Wan, Michael A Sheard, Jianping Sun, Jeremy R Jackson, Jemily Malvar, Yibing Xu, Larry Wang, Richard Sposto, Eugene S Kim, Shahab Asgharzadeh, Robert C Seeger
PURPOSE: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. EXPERIMENTAL DESIGN: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis...
October 10, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Benedetta Pignoloni, Cinzia Fionda, Valentina Dell'Oste, Anna Luganini, Marco Cippitelli, Alessandra Zingoni, Santo Landolfo, Giorgio Gribaudo, Angela Santoni, Cristina Cerboni
Elimination of virus-infected cells by cytotoxic lymphocytes is triggered by activating receptors, among which NKG2D and DNAM-1/CD226 play an important role. Their ligands, that is, MHC class I-related chain (MIC) A/B and UL16-binding proteins (ULBP)1-6 (NKG2D ligand), Nectin-2/CD112, and poliovirus receptor (PVR)/CD155 (DNAM-1 ligand), are often induced on virus-infected cells, although some viruses, including human CMV (HCMV), can block their expression. In this study, we report that infection of different cell types with laboratory or low-passage HCMV strains upregulated MICA, ULBP3, and PVR, with NKG2D and DNAM-1 playing a role in NK cell-mediated lysis of infected cells...
October 12, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Geok Choo Sim, Chengwen Liu, Ena Wang, Hui Liu, Caitlin Creasy, Zhimin Dai, Willem W Overwijk, Jason Roszik, Francesco M Marincola, Patrick Hwu, Elizabeth A Grimm, Laszlo G Radvanyi
Clinical responses to high-dose IL-2 therapy are limited due to selective expansion of CD4+CD25+oxp3+ T-regulatory cells (Tregs) especially ICOS+Tregs, rather than NK cells and effector T cells. These ICOS+Tregs are highly suppressive and constitutively express high levels of IL-2Ralpha (CD25) and CD39. Here, we characterized the effect of a mutant form of IL-2 (F42K), which preferentially binds to the lower affinity IL-2Rbetagamma with reduced binding to CD25, on Tregs, effector NK cells, and T-cell subsets...
October 3, 2016: Cancer Immunology Research
Katarina M Mirjačić Martinović, Nada Lj Babović, Radan R Džodić, Vladimir B Jurišić, Aleksandra Z Ninković, Gordana M Konjević
Considering tumor-mediated suppression of natural killer (NK) cells, the aim of this study was to investigate the in-vitro effects of interleukin (IL)-2 and IL-12, as immunostimulatory cytokines, on the functional and receptor characteristics of NK cells and their subsets in healthy control (HC) and metastatic melanoma (MM) patients. Peripheral blood mononuclear cells of 27 HC and 35 MM patients were stimulated in vitro with IL-2, IL-12, and their combination for functional and phenotypic analysis. IL-2, IL-12, and primarily their combination, significantly induced NK cell activity, CD107a degranulation marker, and perforin expression in NK cells and their subsets in HC and MM patients...
September 10, 2016: Melanoma Research
Conor J Kearney, Kelly M Ramsbottom, Ilia Voskoboinik, Phillip K Darcy, Jane Oliaro
Acute myeloid leukemia (AML) is associated with poor natural killer (NK) cell function through aberrant expression of NK-cell-activating receptors and their ligands on tumor cells. These alterations are thought to promote formation of inhibitory NK-target cell synapses, in which killer cell degranulation is attenuated. Allogeneic stem cell transplantation can be effective in treating AML, through restoration of NK cell lytic activity. Similarly, agents that augment NK-cell-activating signals within the immunological synapse may provide some therapeutic benefit...
August 2016: Oncoimmunology
Huaijian Guo, Stacey A Cranert, Yan Lu, Ming-Chao Zhong, Shaohua Zhang, Jun Chen, Rui Li, Sarah E Mahl, Ning Wu, Dominique Davidson, Stephen N Waggoner, André Veillette
Signaling lymphocytic activation molecule (SLAM) family receptors (SFRs) can mediate either activating or inhibitory effects during natural killer cell (NK cell) activation. In this study, we addressed the global role, regulation, and mechanism of action of the SLAM family in NK cells by analyzing a mouse lacking the entire ∼400-kilobase Slam locus, which encodes all six SFRs and CD48, the ligand of SFR 2B4. This mouse displayed enhanced NK cell activation responses toward hematopoietic target cells. Analyses of mice lacking individual SFRs showed that the inhibitory function of the Slam locus was due solely to 2B4 and was not influenced positively or negatively by other SFRs...
September 19, 2016: Journal of Experimental Medicine
Tihana Lenac Rovis, Paola Kucan Brlic, Noa Kaynan, Vanda Juranic Lisnic, Ilija Brizic, Stefan Jordan, Adriana Tomic, Daria Kvestak, Marina Babic, Pinchas Tsukerman, Marco Colonna, Ulrich Koszinowski, Martin Messerle, Ofer Mandelboim, Astrid Krmpotic, Stipan Jonjic
The poliovirus receptor (PVR) is a ubiquitously expressed glycoprotein involved in cellular adhesion and immune response. It engages the activating receptor DNAX accessory molecule (DNAM)-1, the inhibitory receptor TIGIT, and the CD96 receptor with both activating and inhibitory functions. Human cytomegalovirus (HCMV) down-regulates PVR expression, but the significance of this viral function in vivo remains unknown. Here, we demonstrate that mouse CMV (MCMV) also down-regulates the surface PVR. The m20.1 protein of MCMV retains PVR in the endoplasmic reticulum and promotes its degradation...
August 22, 2016: Journal of Experimental Medicine
Tomoko Inoue, Katsuyuki Adachi, Kei Kawana, Ayumi Taguchi, Takeshi Nagamatsu, Asaha Fujimoto, Kensuke Tomio, Aki Yamashita, Satoko Eguchi, Haruka Nishida, Hiroe Nakamura, Masakazu Sato, Mitsuyo Yoshida, Takahide Arimoto, Osamu Wada-Hiraike, Katsutoshi Oda, Yutaka Osuga, Tomoyuki Fujii
Cancer-associated fibroblasts (CAFs) play an important role in cancer expansion and progression in tumor microenvironment (TME), via both direct and indirect interactions. Natural killer (NK) cells play a crucial role in anticancer immunity. We investigated the inhibitory effects of CAFs on NK cell activity. CAFs were isolated from endometrial cancer tissue, while normal endometrial fibroblasts (NEFs) were obtained from normal endometrium with no pathological abnormality. NK cells were obtained from allogenic healthy volunteers...
October 2016: International Journal of Oncology
Joanna S Kritikou, Carin I M Dahlberg, Marisa A P Baptista, Arnika K Wagner, Pinaki P Banerjee, Lavesh Amar Gwalani, Cecilia Poli, Sudeepta K Panda, Klas Kärre, Susan M Kaech, Fredrik Wermeling, John Andersson, Jordan S Orange, Hanna Brauner, Lisa S Westerberg
To kill target cells, natural killer (NK) cells organize signaling from activating and inhibitory receptors to form a lytic synapse. Wiskott-Aldrich syndrome (WAS) patients have loss-of-function mutations in the actin regulator WASp and suffer from immunodeficiency with increased risk to develop lymphoreticular malignancies. NK cells from WAS patients fail to form lytic synapses, however, the functional outcome in vivo remains unknown. Here, we show that WASp KO NK cells had decreased capacity to degranulate and produce IFNγ upon NKp46 stimulation and this was associated with reduced capacity to kill MHC class I-deficient hematopoietic grafts...
2016: Scientific Reports
Salima Sadallah, Laurent Schmied, Ceylan Eken, Hojjatollah Nozad Charoudeh, Francesca Amicarella, Jürg A Schifferli
Platelet (PLT) transfusions are potentially life saving for individuals with low PLT numbers; however, previous work revealed that PLT transfusions are associated with increased infection risk. During storage, PLT intended for transfusion continuously shed ectosomes (Ecto) from their surface, which express immunomodulatory molecules like phosphatidylserine or TGF-β1. Recently, PLT-Ecto were shown to reduce proinflammatory cytokine release by macrophages and to favor the differentiation of naive T cells toward regulatory T cells...
September 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Claudia Cappel, Sabine Huenecke, Anica Suemmerer, Stephanie Erben, Eva Rettinger, Verena Pfirrmann, Annekathrin Heinze, Olga Zimmermann, Thomas Klingebiel, Evelyn Ullrich, Peter Bader, Melanie Bremm
BACKGROUND: Neuroblastoma (NB) is the most common solid extracranial tumor in childhood. Despite advances in therapy, the prognosis is poor and optimized therapies are urgently needed. Therefore, we investigated the antitumor potential of interleukin-15 (IL-15)-activated cytokine-induced killer (CIK) cells against different NB cell lines. PROCEDURE: CIK cells were generated from peripheral blood mononuclear cells by the stimulation with interferon-γ (IFN-γ), IL-2, OKT-3 and IL-15 over a period of 10-12 days...
July 19, 2016: Pediatric Blood & Cancer
Liu-Sheng Peng, Fang-Yuan Mao, Yong-Liang Zhao, Ting-Ting Wang, Na Chen, Jin-Yu Zhang, Ping Cheng, Wen-Hua Li, Yi-Pin Lv, Yong-Sheng Teng, Gang Guo, Ping Luo, Weisan Chen, Quan-Ming Zou, Yuan Zhuang
CD3+CD56+ natural killer T (NKT)-like cells are a group of CD3+ T cells sharing characteristics of NK and T cells and constitute a major component of host anti-tumor immune response in human cancer. However, the nature, function and clinical relevance of CD3+CD56+ NKT-like cells in human gastric cancer (GC) remain unclear. In this study, we showed that the frequencies of CD3+CD56+NKT-like cells in GC tumors were significantly decreased and low levels of tumor-infiltrating CD3+CD56+ NKT-like cells were positively correlated with poor survival and disease progression...
July 8, 2016: Oncotarget
Zachary B Davis, Bharatwaj Sowrirajan, Andrew Cogswell, Jeffrey P Ward, Vicente Planelles, Edward Barker
Activation of primary CD4+ T-cells induces the CD155 but not the CD112 ligands for the natural killer (NK) cell activation receptor (aNKR) CD226 [DNAX accessory molecule-1 (DNAM-1)]. We hypothesize that HIV productively infects activated CD4+ T-cells and makes itself vulnerable to NK cell-mediated lysis when CD155 on infected T-cells engages DNAM-1. The primary objective of this study is to determine whether CD155 alone or together with NKG2D ligands triggers autologous NK cell lysis of HIV-infected T-cells and whether HIV modulates CD155...
June 13, 2016: AIDS Research and Human Retroviruses
Minoru Kanaya, Kazuko Shibuya, Rei Hirochika, Miyoko Kanemoto, Kazuteru Ohashi, Masafumi Okada, Yukiko Wagatsuma, Yukiko Cho, Hiroshi Kojima, Takanori Teshima, Masahiro Imamura, Hisashi Sakamaki, Akira Shibuya
Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because diagnosis of aGVHD is exclusively based on clinical symptoms and pathological findings, reliable and noninvasive laboratory tests for accurate diagnosis are required. An activating immunoreceptor, DNAM-1 (CD226), is expressed on T cells and natural killer cells and is involved in the development of aGVHD. Here, we identified a soluble form of DNAM-1 (sDNAM-1) in human sera...
2016: PloS One
Catherine A Forbes, Anthony A Scalzo, Mariapia A Degli-Esposti, Jerome D Coudert
NK cells possess inhibitory receptors that are responsible for self-MHC class I recognition; beyond their inhibitory function, accumulating evidence indicates that such receptors confer NK cell functional competence through an unclear process termed "licensing." Ly49C is the main self-specific inhibitory Ly49 receptor in H-2(b) C57BL/6 (B6) mice. We used B6 Ly49C-transgenic and B6 β2 microglobulin (β2m)-knockout Ly49C-transgenic mice to investigate the impact of licensing through this inhibitory receptor in precursor and mature NK cells...
July 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Hyung-Joon Kwon, Go-Eun Choi, Sangryeol Ryu, Soon Jae Kwon, Sun Chang Kim, Claire Booth, Kim E Nichols, Hun Sik Kim
NF-κB is a key transcription factor that dictates the outcome of diverse immune responses. How NF-κB is regulated by multiple activating receptors that are engaged during natural killer (NK)-target cell contact remains undefined. Here we show that sole engagement of NKG2D, 2B4 or DNAM-1 is insufficient for NF-κB activation. Rather, cooperation between these receptors is required at the level of Vav1 for synergistic NF-κB activation. Vav1-dependent synergistic signalling requires a separate PI3K-Akt signal, primarily mediated by NKG2D or DNAM-1, for optimal p65 phosphorylation and NF-κB activation...
2016: Nature Communications
Catharina C Gross, Andreas Schulte-Mecklenbeck, Anna Rünzi, Tanja Kuhlmann, Anita Posevitz-Fejfár, Nicholas Schwab, Tilman Schneider-Hohendorf, Sebastian Herich, Kathrin Held, Matea Konjević, Marvin Hartwig, Klaus Dornmair, Reinhard Hohlfeld, Tjalf Ziemssen, Luisa Klotz, Sven G Meuth, Heinz Wiendl
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood-brain barrier, CD56(bright) NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals...
May 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
Andrea Acebes-Huerta, Seila Lorenzo-Herrero, Alicia R Folgueras, Leticia Huergo-Zapico, Carlos Lopez-Larrea, Alejandro López-Soto, Segundo Gonzalez
Formation of polyploid or aneuploid cells is a pathological hallmark of malignant tumors. Cell cycle checkpoint mechanisms play a crucial role in ensuring genomic integrity during mitosis, avoiding the generation of aneuploid cells. Additionally, cancer cell DNA ploidy is subjected to extrinsic controls operated by activation of adaptive immune responses mediated by T cells. NK cells exert a central role in the innate anticancer immunity; however, the mechanisms involved in the recognition of tumor cells by NK cells have not been fully elucidated...
February 2016: Oncoimmunology
Akiko Iguchi-Manaka, Genki Okumura, Hiroshi Kojima, Yukiko Cho, Rei Hirochika, Hiroko Bando, Toyomi Sato, Hiroyuki Yoshikawa, Hisato Hara, Akira Shibuya, Kazuko Shibuya
Emerging evidence suggests that DNAM-1 (CD226) play an important role in the recognition of tumor cells and their lysis by cytotoxic T lymphocytes (CTL) and NK cells. Although the DNAM-1 ligand CD155 is ubiquitously expressed in various tissues, many human tumors significantly upregulate the expression of CD155; DNAM-1 on CTL and NK cells may be involved in tumor immunity. However, unlike those in mice, human tissues also express soluble isoforms of CD155 (sCD155) that lack the transmembrane region. Here, we show that sCD155 levels were significantly higher in the sera of 262 patients with lung, gastrointestinal, breast, and gynecologic cancers than in sera from healthy donors...
2016: PloS One
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