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Nk cells AND pancreatic cancer

Naibin Yang, Shanshan Li, Guoxiang Li, Shengguo Zhang, Xinyue Tang, Shunlan Ni, Xiaomin Jian, Cunlai Xu, Jiayin Zhu, Mingqin Lu
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. As vectors for intercellular information exchange, the potential role of extracellular vesicles (EVs) in HCC formation, progression and therapy has been widely investigated. In this review, we explore the current status of the researches in this field. Altogether there is undeniable evidence that EVs play a crucial role in HCC development, metastasis. Moreover, EVs have shown great potential as drug delivery systems (DDSs) for the treatment of HCC...
October 4, 2016: Oncotarget
Yun-Peng Peng, Chun-Hua Xi, Yi Zhu, Ling-Di Yin, Ji-Shu Wei, Jing-Jing Zhang, Xin-Chun Liu, Song Guo, Yue Fu, Yi Miao
The progression of pancreatic cancer (PC) is significantly associated with tumor immune escape, which may be associated with nature killer (NK) cell dysfunction. CD226, CD96, and TIGIT, which share the ligand CD155, play important roles in the regulation of NK cell function. The present study was conducted to investigate the roles of these molecules in NK cells from PC patients. Expression of these molecules on NK cells was detected from samples of 92 pancreatic cancer patients and 40 healthy controls. The expression of CD155 was also evaluated by immunohistochemistry in 88 pancreatic cancer tissues...
September 10, 2016: Oncotarget
Sonja Textor, Felicitas Bossler, Kai-Oliver Henrich, Moritz Gartlgruber, Julia Pollmann, Nathalie Fiegler, Annette Arnold, Frank Westermann, Nina Waldburger, Kai Breuhahn, Sven Golfier, Mathias Witzens-Harig, Adelheid Cerwenka
Natural Killer (NK) cells are innate effector cells that are able to recognize and eliminate tumor cells through engagement of their surface receptors. NKp30 is a potent activating NK cell receptor that elicits efficient NK cell-mediated target cell killing. Recently, B7-H6 was identified as tumor cell surface expressed ligand for NKp30. Enhanced B7-H6 mRNA levels are frequently detected in tumor compared to healthy tissues. To gain insight in the regulation of expression of B7-H6 in tumors, we investigated transcriptional mechanisms driving B7-H6 expression by promoter analyses...
July 2016: Oncoimmunology
Xiansheng Lin, Mei Huang, Fang Xie, Hangcheng Zhou, Ji Yang, Qiang Huang
Due to early onset of local invasion and distant metastasis, pancreatic cancer is the most lethal human malignant tumor, with a 5 year survival rate of less than 5%. As a effective chemotherapy drug for pancreatic cancer patients, gemcitabine is reported to inhibit cell proliferation as a nucleotide analog. In this study, we investigated the role of gemcitabine in immune regulation of pancreatic cancer. Our data showed that the level of soluble ULBP2 (sULBP2), a ligand of NKG2D receptor, decreased in the supernatants of pancreatic cancer cell lines when gemcitabine was added, and sULBP2 level correlated with NK92 cells cytotoxicity to pancreatic cancer cell lines...
September 1, 2016: Oncotarget
Paul F Rühle, Rainer Fietkau, Udo S Gaipl, Benjamin Frey
The monitoring of immune cells gained great significance in prognosis and prediction of therapy responses. For analyzing blood samples, the multicolor flow cytometry has become the method of choice as it combines high specificity on single cell level with multiple parameters and high throughput. Here, we present a modular assay for the detailed immunophenotyping of blood (DIoB) that was optimized for an easy and direct application in whole blood samples. The DIoB assay characterizes 34 immune cell subsets that circulate the peripheral blood including all major immune cells such as T cells, B cells, natural killer (NK) cells, monocytes, dendritic cells (DCs), neutrophils, eosinophils, and basophils...
2016: International Journal of Molecular Sciences
Marcela D'Alincourt Salazar, Edwin R Manuel, Weimin Tsai, Massimo D'Apuzzo, Leanne Goldstein, Bruce R Blazar, Don J Diamond
Despite the clinical success of anti-PD1 antibody (α-PD1) therapy, the immune mechanisms contributing to the antineoplastic response remain unclear. Here, we describe novel aspects of the immune response involved in α-PD1-induced antitumor effects using an orthotopic Kras (G12D)/p53(R172H)/Pdx1-Cre (KPC) model of pancreatic ductal adenocarcinoma (PDA). We found that positive therapeutic outcome involved both the innate and adaptive arms of the immune system. Adoptive transfer of total splenocytes after short-term (3 d) but not long-term (28 d) PD1 blockade significantly extended survival of non-treated tumor-bearing recipient mice...
June 2016: Oncoimmunology
Marc Schwartz, Yu Zhang, Joseph D Rosenblatt
The balance between immune effector cells such as T cells and natural killer cells, and immunosuppressive Treg cells, dendritic, myeloid and monocytic sub-populations in the tumor microenvironment acts to calibrate the immune response to malignant cells. Accumulating evidence is pointing to a role for B cells in modulating the immune response to both solid tumors and hematologic cancer. Evidence from murine autoimmune models has defined B regulatory cell (Breg) subsets that express cytokines such as IL-10, TGF-β, and/or express immune regulatory ligands such as PD-L1, which can suppress T cell and/or natural killer cell responses...
2016: Journal for Immunotherapy of Cancer
Elizabeth L McMichael, Alena C Jaime-Ramirez, Kristan D Guenterberg, Eric Luedke, Lakhvir S Atwal, Amanda Campbell, Zhiwei Hu, Armika S Tatum, Sri Vidya Kodadasula, Xiaokui Mo, Susheela Tridandapani, Mark Bloomston, E Christopher Ellison, Terence M Williams, Tanios Bekaii-Saab, William E Carson
PURPOSE: Alternative strategies to EGFR blockage by mAbs is necessary in order to improve the efficacy of therapy in patients with locally advanced or metastatic pancreatic cancer. One such strategy includes the use of NK cells to clear cetuximab-coated tumor cells, as need for novel therapeutic approaches to enhance the efficacy of cetuximab is evident. We show that IL-21 enhances NK cell-mediated effector functions against cetuximab-coated pancreatic tumor cells irrespective of KRAS mutation status...
July 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Xingjun Guo, Lei Zheng, Jianxin Jiang, Yan Zhao, Xin Wang, Ming Shen, Feng Zhu, Rui Tian, Hengjian Shi, Meng Xu, Xu Li, Feng Peng, Hang Zhang, Yechen Feng, Yu Xie, Xiaodong Xu, Wei Jia, Ruizhi He, Chencheng Xie, Jun Hu, Dawei Ye, Min Wang, Renyi Qin
PURPOSE: We sought to find new immune-based treatments for pancreatic cancer (PC). EXPERIMENTAL DESIGN: We detected interleukin (IL)-18 expression in plasma and specimens from patients with PC. We then investigated whether IL-18 had a therapeutic effect for PC in vitro and in vivo, and any underlying mechanisms. RESULTS: Higher plasma IL-18 was associated with longer overall survival, but higher IL-18 in PC tissues was associated with shorter overall survival and increased invasion and metastasis...
June 13, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sebastian Lundgren, Carl Fredrik Warfvinge, Jacob Elebro, Margareta Heby, Björn Nodin, Agnieszka Krzyzanowska, Anders Bjartell, Karin Leandersson, Jakob Eberhard, Karin Jirström
BACKGROUND: Natural killer (NK) cells and NK T cells (NKT) are vital parts of tumour immunosurveillance. However, their impact on prognosis and chemotherapy response in periampullary adenocarcinoma, including pancreatic cancer, has not yet been described. METHODS: Immune cell-specific expression of CD56, CD3, CD68 and CD1a was analysed by immunohistochemistry on tissue microarrays with tumours from 175 consecutive cases of periampullary adenocarcinoma, 110 of pancreatobiliary type (PB-type) and 65 of intestinal type (I-type) morphology...
2016: PloS One
Ran Cui, Wen Yue, Edmund C Lattime, Mark N Stein, Qing Xu, Xiang-Lin Tan
The tumor microenvironment is replete with cells that evolve with and provide support to tumor cells during the transition to malignancy. The hijacking of the immune system in the pancreatic tumor microenvironment is suggested to contribute to the failure to date to produce significant improvements in pancreatic cancer survival by various chemotherapeutics. Regulatory T cells, myeloid derived suppressor cells, and fibroblasts, all of which constitute a complex ecology microenvironment, can suppress CD8+ T cells and NK cells, thus inhibiting effector immune responses...
May 15, 2016: Oncotarget
Steven K Grossenbacher, Robert J Canter, William J Murphy
Advances in cancer immunotherapy are leading to its increasing and successful application for the treatment of solid-tissue cancers. Despite the recent advances there are still significant barriers, in particular, evidence for significant tumor heterogeneity, both genetic and epigenetic that limit long-term efficacy. Subpopulations of "stem-like" tumor cells have been identified in nearly all human malignancies based on both morphologic and functional criteria. Also called cancer stem cells or CSCs, these quiescent cells display enhanced tumorigenic potential and are capable of repopulating tumors in the wake of traditional cytoreductive therapies...
2016: Journal for Immunotherapy of Cancer
Anna K Kozlowska, Kawaljit Kaur, Paytsar Topchyan, Anahid Jewett
Based on data obtained from oral, pancreatic and lung cancers, glioblastoma, and melanoma, we have established that natural killer (NK) cells target cancer stem-like cells (CSCs). CSCs displaying low MHC class I, CD54, and PD-L1 are killed by cytotoxic NK cells and are differentiated by split anergized NK cells through both membrane bound and secreted forms of TNF-α and IFN-γ. NK cells select and differentiate both healthy and transformed stem-like cells, resulting in target cell maturation and shaping of their microenvironment...
July 2016: Cancer Immunology, Immunotherapy: CII
Cheng-Jeng Tai, Hang Wang, Chien-Kai Wang, Chen-Jei Tai, Ming-Te Huang, Chih-Hsiung Wu, Ray-Jade Chen, Li-Jen Kuo, Po-Lei Wei, Yu-Jia Chang, Chun-Chao Chang, Hung-Yi Chiou, Chang-Jer Wu
Pancreatic cancer remains the fourth leading cause of cancer-related death in the USA with a 5-year survival rate of 5 %. The effects of epidermal growth factor receptor and vascular endothelial growth factor A blockade with chemotherapy on pancreatic tumor growth were examined. Mice bearing human PANC-1 cell xenografts were divided into three groups: T-CR (gemcitabine, cisplatin, and 5-fluorouracil), T-TR (cetuximab, bevacizumab, gemcitabine, cisplatin, and 5-fluorouracil), and vehicle control (T). The therapies were administered via intraperitoneal injections every 4 days for seven cycles from 7 weeks after cancer cell implantation...
March 19, 2016: Clinical and Experimental Medicine
Yang Feng, Yanping Wang, Zhongyu Zhu, Wei Li, Robyn T Sussman, Michael Randall, Kristopher R Bosse, John M Maris, Dimiter S Dimitrov
CD56 (NCAM, neural cell adhesion molecule) is over-expressed in many tumor types, including neuroblastoma, multiple myeloma, small cell lung cancer, ovarian cancer, acute myeloid leukemia, NK-T lymphoma, neuroendocrine cancer and pancreatic cancer. Using phage display, we identified 2 high-affinity anti-CD56 human monoclonal antibodies (mAbs), m900 and m906, which bound to spatially separated non-overlapping epitopes with similar affinity (equilibrium dissociation constant 2.9 and 4.5 nM, respectively). m900 bound to the membrane proximal fibronectin type III-like domains, whereas m906 bound to the N-terminal IgG-like domains...
May 2016: MAbs
Jun-ichi Masuyama, Takashi Murakami, Sanju Iwamoto, Sanehiko Fujita
BACKGROUND AIMS: This study developed a new method to expand CD3(-)CD56(+) natural killer (NK) cells from human peripheral blood mononuclear cells (PBMCs) without feeder cells for clinical trials. METHODS: PBMCs from healthy subjects were co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies and cultured for 14 days in newly developed NKGM-1 medium containing autologous plasma and interleukin-2. Expanded NK cells were examined for cell number, phenotype, in vitro and in vivo cytotoxicity and interferon (IFN)-γ secretion...
January 2016: Cytotherapy
Erik Ames, Robert J Canter, Steven K Grossenbacher, Stephanie Mac, Mingyi Chen, Rachel C Smith, Takeshi Hagino, Jessica Perez-Cunningham, Gail D Sckisel, Shiro Urayama, Arta M Monjazeb, Ruben C Fragoso, Thomas J Sayers, William J Murphy
Increasing evidence supports the hypothesis that cancer stem cells (CSCs) are resistant to antiproliferative therapies, able to repopulate tumor bulk, and seed metastasis. NK cells are able to target stem cells as shown by their ability to reject allogeneic hematopoietic stem cells but not solid tissue grafts. Using multiple preclinical models, including NK coculture (autologous and allogeneic) with multiple human cancer cell lines and dissociated primary cancer specimens and NK transfer in NSG mice harboring orthotopic pancreatic cancer xenografts, we assessed CSC viability, CSC frequency, expression of death receptor ligands, and tumor burden...
October 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Miguel Muñoz, Rafael Coveñas
Pancreatic cancer (PC) is the fourth leading cause of cancer related-deaths in both men and women, and the 1- and 5-year relative survival rates are 25% and 6%, respectively. It is known that smoking, alcoholism and psychological stress are risk factors that can promote PC and increase PC progression. To date, the prevention of PC is crucial because there is no curative treatment. After binding to the neurokinin-1 (NK-1) receptor (a receptor coupled to the stimulatory G-protein Gαs that activates adenylate cyclase), the peptide substance P (SP)-at high concentrations-is involved in many pathophysiological functions, such as depression, smoking, alcoholism, chronic inflammation and cancer...
2015: Cancers
Ramesh C Halder, Anasheh Almasi, Bien Sagong, Jessica Leung, Anahid Jewett, Milan Fiala
Pancreatic cancer has a poor prognosis attributed in part to immune suppression and deactivation of natural killer (NK) cells. Curcuminoids have a potential for improving the therapy of pancreatic cancer given promising results in cancer models and a clinical trial, but their oral absorption is limited. Our objective in this study is to show curcuminoid anti-oncogenic effects alone and together with human NK cells. We tested curcuminoids in an emulsion of ω-3 fatty acids and anti-oxidants ("Smartfish") regarding their direct cytocidal effect and enhancement of the cytocidal activity of NK cells in pancreatic ductal adenocarcinoma (PDAC) cells (Mia Paca 2 and L3...
2015: Frontiers in Physiology
Hanno M Specht, Norbert Ahrens, Christiane Blankenstein, Thomas Duell, Rainer Fietkau, Udo S Gaipl, Christine Günther, Sophie Gunther, Gregor Habl, Hubert Hautmann, Matthias Hautmann, Rudolf Maria Huber, Michael Molls, Robert Offner, Claus Rödel, Franz Rödel, Martin Schütz, Stephanie E Combs, Gabriele Multhoff
Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70...
2015: Frontiers in Immunology
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