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Nk cells AND pancreatic cancer

Orit Berhani, Ariella Glasner, Shira Kahlon, Alexandra Duev-Cohen, Rachel Yamin, Elad Horwitz, Jonatan Enk, Ofra Moshel, Alexandar Varvak, Angel Porgador, Stipan Jonjic, Ofer Mandelboim
Natural killer (NK) cells are innate lymphocytes that efficiently eliminate cancerous and infected cells. NKp46 is an important NK activating receptor shown to participate in recognition and activation of NK cells against pathogens, tumor cells, virally infected cells, and self-cells in autoimmune conditions, including type I and II diabetes. However, some of the NKp46 ligands are unknown and therefore investigating human NKp46 activity and its critical role in NK cell biology is problematic. We developed a unique anti-human NKp46 monocloncal antibody, denoted hNKp46...
February 2019: European Journal of Immunology
Jaemin Lee, Tae Heung Kang, Wonbeak Yoo, Hyunji Choi, Seongyea Jo, Kyungsu Kong, Sang-Rae Lee, Sun-Uk Kim, Ji-Su Kim, Duck Cho, Janghwan Kim, Jeong-Yoon Kim, Eun-Soo Kwon, Seokho Kim
Natural killer (NK) cells are primary immune cells that target cancer cells and can be used as a therapeutic agent against pancreatic cancer. Despite the usefulness of NK cells, NK-cell therapy is limited by tumor cell inhibition of NK-cell homing to tumor sites, thereby preventing a sustained antitumor immune response. One approach to successful cancer immunotherapy is to increase trafficking of NK cells to tumor tissues. Here, we developed an antibody-based NK-cell-homing protein, named NK-cell-recruiting protein-conjugated antibody (NRP-body)...
February 2019: Cancer Immunology Research
Xiaoyu An, Xuesong Ouyang, Hui Zhang, Tingting Li, Yu-Yang Huang, Zhiyuan Li, Demin Zhou, Qi-Xang Li
Homograft (syngeneic) tumors are the workhorse of today's immuno-oncology (I/O) preclinical research. The tumor microenvironment (TME), particularly its immune-components, is vital to the prognosis and prediction of treatment outcomes, especially those of immunotherapy. TME immune-components are composed of different subsets of tumor-infiltrating immune cells assessable by multi-color FACS. Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignances lacking good treatment options, thus an urgent and unmet medical need...
October 9, 2018: Journal of Visualized Experiments: JoVE
Nadia Saadat, Sarah Akhtar, Arvind Goja, Nurul H Razalli, Andreea Geamanu, Doina David, Yimin Shen, Smiti Vaid Gupta
Pancreatic cancer (PC) patients have poor prognosis and survival rate. Gemcitabine, the drug of choice has a dismal 15% response rate. Earlier, we reported that Garcinol alone and in combination with gemcitabine showed a dose-dependent favorable response on PC cell lines. This study probes the in vivo effects of dietary Garcinol on PC progression in transgenic PC mice (KPC; K-ras and p53 conditional mutant). KPC male mice were divided into: KC- Control diet; KGr-0.05% Garcinol diet; KGm-Gemcitabine injected; KGG - Garcinol diet + Gemcitabine injected groups...
October 1, 2018: Nutrition and Cancer
Limei Shen, Jingjing Li, Qi Liu, Wantong Song, Xueqiong Zhang, Karthik Tiruthani, Haiyang Hu, Manisit Das, Tyler Jay Goodwin, Rihe Liu, Leaf Huang
In many cancers, the tumor microenvironment (TME) is largely immune suppressive, blocking the antitumor immunity and resulting in immunotherapy resistance. Interleukin 10 (IL-10) is a major player controlling the immunosuppressive TME in different murine tumor models. Increased IL-10 production suppresses intratumoral dendritic cell production of interleukin 12, thereby limiting antitumor cytotoxic T-cell responses and activation of NK cells during therapy. We engineered, formulated, and delivered genes encoding an IL-10 protein trap to change immunosuppressive TME, which could enhance antitumor immunity...
September 28, 2018: ACS Nano
Chao Yang, He Cheng, Yiyin Zhang, Kun Fan, Guopei Luo, Zhiyao Fan, Qiuyi Huang, Yu Lu, Kaizhou Jin, Zhengshi Wang, Xianjun Yu, Chen Liu
INTRODUCTION: Natural killer cells (NK) are often believed to play a positive role in the antitumor immune response. However, this is not the case for patients with advanced pancreatic cancer. This study was performed to determine the unique subtype of "educated" NK cells and their prognostic value in patients with advanced pancreatic cancer. METHODS: We divided 378 eligible patients into a derivation cohort (September 2010 to December 2014, n = 239) and a validation cohort (January 2015 to April 2016, n = 139)...
August 22, 2018: Cancer Immunology, Immunotherapy: CII
Anahid Jewett, Janko Kos, Yuman Fong, Meng-Wei Ko, Tahmineh Safaei, Milica Perišić Nanut, Kawaljit Kaur
We have recently shown that natural killer (NK) cells select and differentiate cancer stem cells (CSCs)/undifferentiated tumors via secreted and membrane bound IFN-gamma (IFN-γ) and TNF-alpha (TNF-α), preventing tumor growth and inducing remodeling of the tumor microenvironment. Since many conventional therapeutic strategies, including chemotherapy and radiotherapy remain fairly unsuccessful in treating CSCs/poorly differentiated tumors, there has been an increasing interest in NK cell-targeted immunotherapy for the treatment of aggressive tumors...
August 3, 2018: Seminars in Cancer Biology
Kawaljit Kaur, Hui-Hua Chang, Paytsar Topchyan, Jessica Morgan Cook, Andre Barkhordarian, Guido Eibl, Anahid Jewett
The combined/synergistic effect of genetic mutation of KRAS in the pancreas and obesity, a life-style factor on suppression of natural killer (NK) cells at the pre-neoplastic stage of pancreatic cancer has not been investigated and is the subject of this report. Obese mice with KRAS (KC) mutation in the pancreas fed with high-fat calorie diet (HFCD) exhibit severe deficiencies in the NK cell expansion and function at the pre-neoplastic stage of pancreatic cancer. Decreased NK cell-mediated cytotoxicity is observed in the peripheral blood, spleen, pancreas, and peri-pancreatic adipose tissue in obese KC mice, whereas in bone marrow an increased NK cell-mediated cytotoxicity is observed when compared to lean WT mice fed with control diet (CD)...
2018: Frontiers in Immunology
E O Ostapchuk, A Kali, N N Belyaev
We studied the role of cytokines TGF-β and TNFα in reduction of the cytolytic activity of NK cells towards tumor cells. Exogenous TGF-β and TNFα reduced the sensitivity of MiaPaCa2 pancreatic adenocarcinoma cells to NK cytotoxicity, which was associated with reduction of ULBP-1 expression and increase of HLA-E, HLA-G, CD155, and CD112 expression on Mia-PaCa2 cells. Changes in the expression of ligands for NK receptors on tumor cells induced by TGF-β and TNFα may contribute to reduction of cytotoxicity of tumor-associated NK cells and thus prevent an adequate antitumor immune response leading to the disease progress...
June 2018: Bulletin of Experimental Biology and Medicine
Edward Hammond, Nicole M Haynes, Carleen Cullinane, Todd V Brennan, Darryn Bampton, Paul Handley, Tomislav Karoli, Fleur Lanksheer, Liwen Lin, Yiping Yang, Keith Dredge
BACKGROUND: Pixatimod (PG545) is a novel clinical-stage immunomodulatory agent capable of inhibiting the infiltration of tumor-associated macrophages (TAMs) yet also stimulate dendritic cells (DCs), leading to activation of natural killer (NK) cells. Preclinically, pixatimod inhibits heparanase (HPSE) which may be associated with its inhibitory effect on TAMs whereas its immunostimulatory activity on DCs is through the MyD88-dependent TLR9 pathway. Pixatimod recently completed a Phase Ia monotherapy trial in advanced cancer patients...
June 14, 2018: Journal for Immunotherapy of Cancer
Hans H Oberg, Christian Kellner, Daniel Gonnermann, Susanne Sebens, Dirk Bauerschlag, Martin Gramatzki, Dieter Kabelitz, Matthias Peipp, Daniela Wesch
An enhanced expression of human epidermal growth factor receptor 2 (HER2, ErbB2) often occurs in an advanced stage of breast, ovarian, gastric or esophageal cancer, and pancreatic ductal adenocarcinoma (PDAC). Commonly, HER2 expression is associated with poor clinical outcome or chemoresistance in ovarian and breast cancer patients. Treatment with humanized anti-HER2 monoclonal antibodies, such as trastuzumab or pertuzumab, has improved the outcome of patients with HER2-positive metastatic gastric or breast cancer, but not all patients benefit...
2018: Frontiers in Immunology
O Adotevi, Y Godet, J Galaine, Z Lakkis, I Idirene, J M Certoux, M Jary, R Loyon, C Laheurte, S Kim, A Dormoy, F Pouthier, C Barisien, F Fein, P Tiberghien, X Pivot, S Valmary-Degano, C Ferrand, P Morel, E Delabrousse, C Borg
Despite successful introduction of NK-based cellular therapy in the treatment of myeloid leukemia, the potential use of NK alloreactivity in solid malignancies is still elusive. We performed a phase I clinical trial to assess the safety and efficacy of in situ delivery of allogeneic NK cells combined with cetuximab in liver metastasis of gastrointestinal origin. The conditioning chemotherapy was administrated before the allogeneic NK cells injection via hepatic artery. Three escalating doses were tested (3...
2018: Oncoimmunology
Jonas R M Van Audenaerde, Geert Roeyen, Phillip K Darcy, Michael H Kershaw, M Peeters, Evelien L J Smits
Pancreatic cancer is among the three deadliest cancers worldwide with the lowest 5-year survival of all cancers. Despite all efforts, therapeutic improvements have barely been made over the last decade. Even recent highly promising targeted and immunotherapeutic approaches did not live up to their expectations. Therefore, other horizons have to be explored. Natural Killer (NK) cells are gaining more and more interest as a highly attractive target for cancer immunotherapies, both as pharmaceutical target and for cell therapies...
September 2018: Pharmacology & Therapeutics
Constantinos Roufas, Dimitrios Chasiotis, Anestis Makris, Christodoulos Efstathiades, Christos Dimopoulos, Apostolos Zaravinos
Background: Recently, immune-checkpoint blockade has shown striking clinical results in different cancer patients. However, a significant inter-individual and inter-tumor variability exists among different cancers. The expression of the toxins granzyme A (GZMA) and perforin 1 (PRF1), secreted by effector cytotoxic T cells and natural killer (NK) cells, were recently used as a denominator of the intratumoral immune cytolytic activity (CYT). These levels are significantly elevated upon CD8+ T-cell activation as well as during a productive clinical response against immune-checkpoint blockade therapies...
2018: Frontiers in Oncology
Andrew Stiff, Prashant Trikha, Bethany Mundy-Bosse, Elizabeth McMichael, Thomas A Mace, Brooke Benner, Kari Kendra, Amanda Campbell, Shalini Gautam, David Abood, Ian Landi, Vincent Hsu, Megan Duggan, Robert Wesolowski, Matthew Old, John Harrison Howard, Lianbo Yu, Nancy Stasik, Thomas Olencki, Natarajan Muthusamy, Susheela Tridandapani, John C Byrd, Michael Caligiuri, William E Carson
Purpose: mAbs are used to treat solid and hematologic malignancies and work in part through Fc receptors (FcRs) on natural killer cells (NK). However, FcR-mediated functions of NK cells from patients with cancer are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy. Experimental Design: Cocultures of autologous NK cells and MDSC from patients with cancer were used to study the effect of myeloid-derived suppressor cells (MDSCs) on NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro Mouse breast cancer models were utilized to study the effect of MDSCs on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and an MDSC-targeting agent...
April 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jeffrey S Miller, Chihiro Morishima, Douglas G McNeel, Manish R Patel, Holbrook E K Kohrt, John A Thompson, Paul M Sondel, Heather A Wakelee, Mary L Disis, Judith C Kaiser, Martin A Cheever, Howard Streicher, Steven P Creekmore, Thomas A Waldmann, Kevin C Conlon
Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8+ T-cell function, the basis for clinical testing. Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday-Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated...
April 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jennifer Brooks, Bettina Fleischmann-Mundt, Norman Woller, Julia Niemann, Silvia Ribback, Kristin Peters, Ihsan Ekin Demir, Nina Armbrecht, Guralp O Ceyhan, Michael P Manns, Thomas C Wirth, Stefan Kubicka, Gunter Bernhardt, Mark J Smyth, Diego F Calvisi, Engin Gürlevik, Florian Kühnel
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and disseminating cancer resistant to therapy, including checkpoint immunotherapies, and early tumor resection and (neo)adjuvant chemotherapy fails to improve a poor prognosis. In a transgenic mouse model of resectable PDAC, we investigated the coordinated activation of T and natural killier (NK) cells in addition to gemcitabine chemotherapy to prevent tumor recurrence. Only neoadjuvant, but not adjuvant treatment with a PD-1 antagonist effectively supported chemotherapy and suppressed local tumor recurrence and improved survival involving both NK and T cells...
January 15, 2018: Cancer Research
A Karlitepe, H Kabadayi, S Vatansever, M Gurdal, C Gunduz, G Ercan
AIM: The aim of this study is to investigate the effects of miR150 transfection on NK-like cells differentiated from adipose tissue derived mesenchymal stem cells (AD-MSCs). METHODS: NK-like cells were differentiated from AD-MSCs and activated by miR150 transfection. Transfected/non-transfected NK-like cells were characterized by immunohistochemical and RT-PCR analyzes. Apoptotic efficiency of the transfected/non-transfected NK-like cells on pancreatic cancer cells PANC1 were determined by TUNEL and RT-PCR...
September 2017: Experimental Oncology
Xiang Zhang, Qiaofei Liu, Quan Liao, Yupei Zhao
Recent years, immunotherapy has turned out to be a promising strategy against tumors. Peripheral dopamine (DA) has important roles in immune system among tumor patients. Accumulated reports demonstrate variable expression and distribution of DA receptors (DRs) in diverse immune cells. Interestingly, peripheral DA also involves in tumor progression and it exerts anticancer effects on immunomodulation, which includes inflammasomes in cancer, function of immune effector cells, such as T lymphocytes, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and natural killer (NK) cells...
2017: Journal of Cancer
Jonas R M Van Audenaerde, Jorrit De Waele, Elly Marcq, Jinthe Van Loenhout, Eva Lion, Johan M J Van den Bergh, Ralf Jesenofsky, Atsushi Masamune, Geert Roeyen, Patrick Pauwels, Filip Lardon, Marc Peeters, Evelien L J Smits
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies. Aiming to overcome this resistance by tackling the stromal shield, we assessed for the first time the capacity of IL-15 stimulated natural killer (NK) cells to kill PSC and pancreatic cancer cells (PCC)...
August 22, 2017: Oncotarget
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