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Alessandra Soriani, Cristiana Borrelli, Biancamaria Ricci, Rosa Molfetta, Alessandra Zingoni, Cinzia Fionda, Silvia Carnevale, Maria Pia Abruzzese, Maria Teresa Petrucci, Maria Rosaria Ricciardi, Giuseppe La Regina, Erica Di Cesare, Patrizia Lavia, Romano Silvestri, Rossella Paolini, Marco Cippitelli, Angela Santoni
The mechanisms that regulate the expression of the NKG2D and DNAM-1 activating ligands are only partially known, but it is now widely established that their expression is finely regulated at transcriptional, post-transcriptional and post-translational level, and involve numerous stress pathways depending on the type of ligand, stressor, and cell context. We show that treatment of Multiple Myeloma (MM) cells with sub-lethal doses of Vincristine (VCR), an anticancer drug that inhibits the assembly of microtubules, stimulates the expression of NKG2D and DNAM-1 activating ligands, rendering these cells more susceptible to NK cell-mediated killing...
2017: Oncoimmunology
Xiao-Hui Chen, Lin-Lin Lu, Hong-Peng Ke, Zong-Cai Liu, Hai-Fang Wang, Wei Wei, Yi-Fei Qi, Hong-Sheng Wang, Shao-Hui Cai, Jun Du
Natural killer (NK) cells play an important role in preventing cancer development. NK group 2 member D (NKG2D) is an activating receptor expressed in the membrane of NK cells. Tumour cells expressing NKG2DL become susceptible to an immune-dependent rejection mainly mediated by NK cells. The paradoxical roles of transforming growth factor beta (TGF-β) in regulation of NKG2DL are presented in many studies, but the mechanism is unclear. In this study, we showed that TGF-β up-regulated the expression of NKG2DLs in both PC3 and HepG2 cells...
February 6, 2017: Journal of Cellular and Molecular Medicine
Trever T Greene, Maria Tokuyama, Giselle M Knudsen, Michele Kunz, James Lin, Alexander L Greninger, Victor R DeFilippis, Joseph L DeRisi, David H Raulet, Laurent Coscoy
Natural Killer (NK) cells are essential for control of viral infection and cancer. NK cells express NKG2D, an activating receptor that directly recognizes NKG2D ligands. These are expressed at low level on healthy cells, but are induced by stresses like infection and transformation. The physiological events that drive NKG2D ligand expression during infection are still poorly understood. We observed that the mouse cytomegalovirus encoded protein m18 is necessary and sufficient to drive expression of the RAE-1 family of NKG2D ligands...
November 22, 2016: ELife
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...
November 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Shirin Mahmoodi, Navid Nezafat, Abolfazl Barzegar, Manica Negahdaripour, Ali R Nikanfar, Nosratollah Zarghami, Younes Ghasemi
Breast cancer (BC) remains as one of the important causes of cancer deaths among women globally. Therefore, finding an effective treatment for BC is really needed. Cancer immunotherapy, as an emerging field, has a notable role in BC therapy. Peptide vaccines possess an outstanding role among different strategies in cancer immunotherapy. In vaccine design for cancer, induction of cellular and humoral immune responses should be considered. In the current study, cytolytic T lymphocytes (CTL) epitopes were evoked from human epidermal growth factor receptor (HER2), mucin 1 protein (MUC1), and heparanase antigenic proteins; and helper T lymphocytes (HTL) epitopes were determined from survivin protein by various immunoinformatics servers...
2016: Current Pharmaceutical Biotechnology
Jiong Chen, Xing-Xing Zhu, Hong Xu, Heng-Zhong Fang, Jin-Qian Zhao
BACKGROUND: Pancreatic cancer is one of the most lethal cancers worldwide, due to the lack of efficient therapy and difficulty in early diagnosis. ULBPs have been shown to behave as important protectors with prognostic significance in various cancers. MATERIALS AND METHODS: Immunohistochemistry and enzyme-linked immunosorbent assays were used to explore the expression of ULBPs in cancer tissue and in serum, while survival analysis was used to evaluate the subsequent clinical value of ULBPs...
2016: OncoTargets and Therapy
Elizabeth R Sturgill, Daniel Malouli, Scott G Hansen, Benjamin J Burwitz, Seongkyung Seo, Christine L Schneider, Jennie L Womack, Marieke C Verweij, Abigail B Ventura, Amruta Bhusari, Krystal M Jeffries, Alfred W Legasse, Michael K Axthelm, Amy W Hudson, Jonah B Sacha, Louis J Picker, Klaus Früh
The natural killer cell receptor NKG2D activates NK cells by engaging one of several ligands (NKG2DLs) belonging to either the MIC or ULBP families. Human cytomegalovirus (HCMV) UL16 and UL142 counteract this activation by retaining NKG2DLs and US18 and US20 act via lysomal degradation but the importance of NK cell evasion for infection is unknown. Since NKG2DLs are highly conserved in rhesus macaques, we characterized how NKG2DL interception by rhesus cytomegalovirus (RhCMV) impacts infection in vivo. Interestingly, RhCMV lacks homologs of UL16 and UL142 but instead employs Rh159, the homolog of UL148, to prevent NKG2DL surface expression...
August 2016: PLoS Pathogens
Ali Khodadadi, Zahra Abdoli, Mehri Ghafourian Boroujerdnia, Mohammad-Ali Assarehzadegan, Mohammad Ghasemi, Saleh Mohaghegh Hazrati, Nader Dashti Gerdabi
INTRODUCTION: Natural killer (NK) cells are a subset of lymphocytes in humans that release cytokines such as tumor necrosis factor alpha and interferon gamma-γ during infection. NKG2D is one of the most important stimulating NK receptors binding MIC-A, MIC-B, and ULBPs, which leads to activation of NK cells against tumor cells. In this study, the authors evaluated the effect of G2 adjuvant on gene expression and delivery of NKG2D receptor on NK cells in peripheral blood. MATERIALS AND METHODS: Peripheral blood mononuclear cells were isolated from venous blood obtained from healthy volunteers after adding G2 adjuvant within 12, 24, and 48 hours of incubation...
May 2016: Cancer Biotherapy & Radiopharmaceuticals
Eric L Hurwitz, Dongmei Li, Jenni Guillen, Michael J Schneider, Joel M Stevans, Reed B Phillips, Shawn P Phelan, Eugene A Lewis, Richard C Armstrong, Maria Vassilaki
OBJECTIVES: The purpose of the study was to compare utilization and charges generated by medical doctors (MD), doctors of chiropractic (DC) and physical therapists (PT) by patterns of care for the treatment of low back pain in North Carolina. METHODS: This was an analysis of low-back-pain-related closed claim data from the North Carolina State Health Plan for Teachers and State Employees from 2000 to 2009. Data were extracted from Blue Cross Blue Shield of North Carolina for the North Carolina State Health Plan using International Classification of Diseases, 9th Revision diagnostic codes for uncomplicated low back pain (ULBP) and complicated low back pain (CLBP)...
May 2016: Journal of Manipulative and Physiological Therapeutics
Hui Feng, Ying Dong, Jing Wu, Yuan Qiao, Ge Zhu, Haofan Jin, Jiuwei Cui, Wei Li, Yong-Jun Liu, Jingtao Chen, Yanqiu Song
Anthracycline-based chemotherapy is a conventional treatment for breast cancer. However, it can negatively affect host immune function and thereby impair patients' quality of life. Boosting the host immune system and reducing the adverse effect of chemotherapy are important for effective cancer treatment. Natural killer (NK) cells stimulate immune responses against cancer; autologous immune enhancement therapy with NK cells prolongs patient survival without significant adverse effects. This study investigated the effects of combined treatment with the anthracycline agent epirubicin (EPI) and NK cells on human breast cancer cells...
2016: American Journal of Translational Research
María V Martínez-Sánchez, Adela Periago, Isabel Legaz, Lourdes Gimeno, Anna Mrowiec, Natividad R Montes-Barqueros, José A Campillo, José M Bolarin, María V Bernardo, María R López-Álvarez, Consuelo González, María C García-Garay, Manuel Muro, Valentin Cabañas-Perianes, Jose L Fuster, Ana M García-Alonso, José M Moraleda, María R Álvarez-Lopez, Alfredo Minguela
Missing self recognition makes cancer sensitive to natural killer cell (NKc) reactivity. However, this model disregards the NKc licensing effect, which highly increases NKc reactivity through interactions of inhibitory killer cell immunoglobulin-like receptors (iKIR) with their cognate HLA-I ligands. The influence of iKIR/HLA-ligand (HLA-C1/C2) licensing interactions on the susceptibility to and progression of plasma cell (PC) dyscrasias was evaluated in 164 Caucasian patients and 286 controls. Compared to controls, myeloma accumulates KIR2DL1(-)L2(+)L3(-) genotypes (2...
April 2016: Oncoimmunology
Guranda Chitadze, Marcus Lettau, Stefanie Luecke, Ting Wang, Ottmar Janssen, Daniel Fürst, Joannis Mytilineos, Daniela Wesch, Hans-Heinrich Oberg, Janka Held-Feindt, Dieter Kabelitz
The interaction of the MHC class I-related chain molecules A and B (MICA and MICB) and UL-16 binding protein (ULBP) family members expressed on tumor cells with the corresponding NKG2D receptor triggers cytotoxic effector functions in NK cells and γδ T cells. However, as a mechanism of tumor immune escape, NKG2D ligands (NKG2DLs) can be released from the cell surface. In this study, we investigated the NKG2DL system in different human glioblastoma (GBM) cell lines, the most lethal brain tumor in adults. Flow cytometric analysis and ELISA revealed that despite the expression of various NKG2DLs only ULBP2 is released as a soluble protein via the proteolytic activity of "a disintegrin and metalloproteases" (ADAM) 10 and 17...
April 2016: Oncoimmunology
Cristina Maccalli, Diana Giannarelli, Filippo Capocefalo, Lorenzo Pilla, Ester Fonsatti, Anna Maria Di Giacomo, Giorgio Parmiani, Michele Maio
Clinical activity was observed in metastatic melanoma (MM) patients treated with ipilimumab (IPI) combined with fotemustine (FTM) in the phase II NIBIT-M1 study. Peripheral blood mononuclear cells (PBMCs) and serum were collected from MM patients at pre- and at weeks 12 and 24 post-treatment. A comprehensive phenotypic and functional immunomonitoring of circulating T cells, and the detection of soluble immunoregulatory molecules was carried out and correlated with clinical outcome. The frequency at baseline and along the treatment of circulating T central memory cells expressing activation/differentiation markers, such as CD3(+)CD4(+)CD45RO(+)BTLA(+), CD3(+)CD4(+)4-1BB or Th17 lymphocytes correlated with the clinical outcome of MM patients...
February 2016: Oncoimmunology
Srinivas Malladi, Danilo G Macalinao, Xin Jin, Lan He, Harihar Basnet, Yilong Zou, Elisa de Stanchina, Joan Massagué
Metastasis frequently develops years after the removal of a primary tumor, from a minority of disseminated cancer cells that survived as latent entities through unknown mechanisms. We isolated latency competent cancer (LCC) cells from early stage human lung and breast carcinoma cell lines and defined the mechanisms that suppress outgrowth, support long-term survival, and maintain tumor-initiating potential in these cells during the latent metastasis stage. LCC cells show stem-cell-like characteristics and express SOX2 and SOX9 transcription factors, which are essential for their survival in host organs under immune surveillance and for metastatic outgrowth under permissive conditions...
March 24, 2016: Cell
Kensuke Shiraishi, Kousaku Mimura, Ley-Fang Kua, Vivien Koh, Lim Kee Siang, Shotaro Nakajima, Hideki Fujii, Asim Shabbir, Wei-Peng Yong, Jimmy So, Seiichi Takenoshita, Koji Kono
BACKGROUND AND METHODS: Natural killer (NK) cells can react with tumor cells through the balance of inhibitory and stimulatory signals between NK cell surface receptors and their ligands, such as MHC class I chain-related A (MICA), MHC class I chain-related B (MICB), and several UL16-binding proteins (ULBPs). In the present study, we evaluated the relationship between NKG2D ligand expression and matrix metalloproteinase (MMP) activity in in vitro culture systems of a panel of gastric cancer cell lines (n = 10) and clinical samples (n = 102)...
December 2016: Journal of Gastroenterology
Yoav Bauman, Nir Drayman, Orly Ben-Nun-Shaul, Alon Vitenstein, Rachel Yamin, Yael Ophir, Ariella Oppenheim, Ofer Mandelboim
Polyomaviruses are a diverse family of viruses which are prevalent in the human population. However, the interactions of these viruses with the immune system are not well characterized. We have previously shown that two human polyomaviruses, JC and BK, use an identical microRNA to evade immune attack by Natural Killer (NK) cells. We showed that this viral microRNA suppresses ULBP3 expression, a stress induced ligand for the killer receptor NKG2D. Here we show that Simian Virus 40 (SV40) also evades NK cell attack through the down regulation of another stress-induced ligand of NKG2D, ULBP1...
March 29, 2016: Oncotarget
Dominik Schmiedel, Julie Tai, Rachel Yamin, Orit Berhani, Yoav Bauman, Ofer Mandelboim
Expression of the stress-induced ligands MICA, MICB and ULBP 1-6 are up-regulated as a cellular response to DNA damage, excessive proliferation or viral infection; thereby, they enable recognition and annihilation by immune cells that express the powerful activating receptor NKG2D. This receptor is present not exclusively, but primarily on NK cells. Knowledge about the regulatory mechanisms controlling ULBP expression is still vague. In this study, we report a direct interaction of the oncogenic RNA binding protein (RBP) IMP3 with ULBP2 mRNA, leading to ULBP2 transcript destabilization and reduced ULBP2 surface expression in several human cell lines...
March 16, 2016: ELife
B González, D Bueno, P M Rubio, S San Román, D Plaza, A Sastre, P García-Miguel, L Fernández, J Valentín, I Martínez, A Pérez-Martínez
INTRODUCTION: Acute myeloid leukaemia (AML) is the second haematological malignancy in the paediatric population, and one of the leading causes of childhood cancer mortality. Survival is currently around 60%, with no improvement in last decades, suggesting that new therapeutic approaches are needed. The anti-leukaemia effect mediated by the lymphocytes and natural killer (NK) cells of the immune system has been established in haematopoietic stem cell transplantation, and also as adoptive immunotherapy after consolidation chemotherapy schemes...
April 2016: Anales de Pediatría: Publicación Oficial de la Asociación Española de Pediatría (A.E.P.)
Lola Fernández-Messina, Hugh T Reyburn, Mar Valés-Gómez
The expression of NKG2D ligands (NKG2D-L) flag stressed cells for immune recognition and destruction. A precise control of the cell surface expression of these proteins is therefore required to ensure an appropriate immune response and it is becoming clear that NKG2D ligand expression is regulated at multiple levels. We now report that the surface stability of the human glycosyl-phosphatidyl-inositol (GPI)-anchored ligand ULBP1 (UL16-binding protein) at the plasma membrane is lower than other ULBP molecules...
May 2016: Immunology and Cell Biology
Carolina Hager Ribeiro, Karina Kramm, Felipe Gálvez-Jirón, Víctor Pola, Marco Bustamante, Hector R Contreras, Andrea Sabag, Macarena Garrido-Tapia, Carolina J Hernández, Roberto Zúñiga, Norberto Collazo, Pablo Hernán Sotelo, Camila Morales, Luis Mercado, Diego Catalán, Juan Carlos Aguillón, María Carmen Molina
Gastric cancer (GC) is the third most common cause of cancer death worldwide. Natural killer cells play an important role in the immune defense against transformed cells. They express the activating receptor NKG2D, whose ligands belong to the MIC and ULBP/RAET family. Although it is well established that these ligands are generally expressed in tumors, the association between their expression in the tumor and gastric mucosa and clinical parameters and prognosis of GC remains to be addressed. In the present study, MICA and MICB expression was analyzed, by flow cytometry, in 23 and 20 pairs of gastric tumor and adjacent non-neoplasic gastric mucosa, respectively...
March 2016: Oncology Reports
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