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Junlin Yao, Dalam Ly, Dzana Dervovic, Linan Fang, Jong Bok Lee, Hyeonjeong Kang, Yu-Hui Wang, Nhu-An Pham, Hongming Pan, Ming-Sound Tsao, Li Zhang
BACKGROUND: The advents of novel immunotherapies have revolutionized the treatment of cancer. Adoptive cellular therapies using chimeric antigen receptor T (CAR-T) cells have achieved remarkable clinical responses in B cell leukemia and lymphoma but the effect on solid tumors including lung cancer is limited. Here we present data on the therapeutic potential of allogeneic CD3+ CD4- CD8- double negative T (DNT) cells as a new cellular therapy for the treatment of lung cancer and underlying mechanisms...
January 22, 2019: Journal for Immunotherapy of Cancer
Giulia Mazzaschi, Francesco Facchinetti, Gabriele Missale, Diana Canetti, Denise Madeddu, Alessandra Zecca, Michele Veneziani, Francesco Gelsomino, Matteo Goldoni, Sebastiano Buti, Paola Bordi, Franco Aversa, Andrea Ardizzoni, Federico Quaini, Marcello Tiseo
INTRODUCTION: A prospective investigation of the circulating immune profile in NSCLC patients receiving nivolumab was performed to identify potentially predictive parameters. METHODS: Flow Cytometry of peripheral blood (PB) CD3+, CD8+, CD4+, NK, Treg and MDSCs was prospectively performed in 31 consecutive advanced NSCLC patients at baseline (T0) and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. Functional molecules (PD-1, CD3ζ, Granzyme B, Perforin), cell proliferation (Ki67) and NK receptors (NKG2 A, NKG2D, NKp30) were also explored...
January 2019: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Beatrice Casu, Alessandra Dondero, Stefano Regis, Fabio Caliendo, Andrea Petretto, Martina Bartolucci, Francesca Bellora, Cristina Bottino, Roberta Castriconi
TGF-β1 is a pleiotropic factor exerting a strong regulatory role in several cell types, including immune cells. In NK cells it profoundly alters the surface expression of crucial activating and chemokine receptors. To understand which soluble signals might better contrast these effects, we cultured human NK cells in the presence of TGF-β1 and different innate and adaptive cytokines, generally referred as "immunostimulatory". These included IL-2, IL-15, IL-21, IL-27, and IL-18. Unexpectedly, IL-18 strengthened rather than contrasting important TGF-β1-mediated functions...
January 11, 2019: Cancers
Allistair A Abraham, Haili Lang, Emily Riehm Meier, Robert S Nickel, Marcus Dean, Nurah Lawal, Barbara Speller-Brown, Yunfei Wang, Leslie Kean, Catherine M Bollard
BACKGROUND: Sickle cell disease (SCD) is increasingly recognized as a red blood cell disorder modulated by abnormally increased inflammation. We have previously shown that in patients with SCD not on a disease-modifying therapy (hydroxyurea or chronic transfusions), natural killer (NK) cell numbers are increased. In the current study, we further investigated the NK cell function to determine if there was evidence of increased activation and cytotoxicity. PROCEDURE: We conducted a cross-sectional study of 44 patients with HbSS/HbSβ0 thalassemia at steady state (hydroxyurea = 13, chronic transfusion = 11, no disease-modifying therapy = 20) and 23 healthy controls...
January 4, 2019: Pediatric Blood & Cancer
Jianhong Zhang, Caroline E Dunk, Oksana Shynlova, Isabella Caniggia, Stephen J Lye
BACKGROUND: Decidual natural killer (dNK) cells are the predominant lymphocytes accumulated at the maternal-fetal interface. Regulatory mechanism of dNK cells in preeclampsia, a gestational complication characterized by high blood pressure and increased proteinuria occurring after 20 weeks pregnancy, is not completely understood. METHODS: Multi-parameter flow cytometry is applied to investigate the phenotype and function of dNK cells freshly isolated from decidual samples or conditionally cultured by TGFb stimulation...
December 19, 2018: EBioMedicine
Alexandre Ivagnès, Meriem Messaoudene, Gautier Stoll, Bertrand Routy, Aurélie Fluckiger, Takahiro Yamazaki, Kristina Iribarren, Connie P M Duong, Laetitia Fend, Anne Caignard, Isabelle Cremer, Axel LeCesne, Julien Adam, Charles Honoré, Olivier Mir, Loïc Chaigneau, Anne Berger, Pierre Validire, Christos Christidis, Valérie Le Brun-Ly, Mark J Smyth, Xavier Mariette, Benoît L Salomon, Guido Kroemer, Sylvie Rusakiewicz, Laurence Zitvogel
Natural Killer (NK) cells control metastatic dissemination of murine tumors and are an important prognostic factor in several human malignancies. However, tumor cells hijack many of the NK cell functional features compromising their tumoricidal activity. Here, we show a deleterious role of the TNFα/TNFR2/BIRC3/TRAF1 signaling cascade in NK cells from the tumor microenvironment (TME). TNFα induces BIRC3/cIAP2 transcripts and reduces NKp46/NCR1 transcription and surface expression on NK cells, promoting metastases dissemination in mice and poor prognosis in GIST patients...
2018: Oncoimmunology
Alexandra Frazao, Meriem Messaoudene, Nicolas Núñez, Nicolas Dulphy, France Roussin, Christine Sedlik, Laurence Zitvogel, Eliane Piaggio, Antoine Toubert, Anne Caignard
Tumor-draining lymph nodes (TD-LNs) are the first site of metastasis of breast cancer (BC). Natural killer (NK) cells that infiltrate TD-LNs (including non-invaded (NI) or metastatic (M)-LNs from BC patients) and NK cells from healthy donor (HD)-LN were characterized, and their phenotype analyzed by flow cytometry. Low percentages of tumor cells invaded M-LNs, and these cells expressed ULBP2 and HLA class I molecules. Although NK cells from paired NI and M-LNs were similar, they expressed different markers compared to HD-LN NK cells...
December 4, 2018: Cancer Immunology Research
Anna Maria Trotta, Sara Santagata, Serena Zanotta, Crescenzo D'Alterio, Maria Napolitano, Giuseppina Rea, Rosa Camerlingo, Fabio Esposito, Elvira Lamantia, Annamaria Anniciello, Giovanni Botti, Nicola Longo, Gerardo Botti, Sandro Pignata, Sisto Perdonà, Stefania Scala
BACKGROUND: Previous evidence demonstrated that restoration of wild type VHL in human renal cancer cells decreased in vitro NK susceptibility. To investigate on the role of tumoral VHL status versus NK capability in renal cancer patients, 51 RCC patients were characterized for VHL mutational status and NK function. METHODS: VHL mutational status was determined by direct DNA sequencing on tumor tissue. NK cytotoxicity was measured against specific target cells K562, VHL-wild type (CAKI-1) and VHL-mutated (A498) human renal cancer cells through externalization of CD107a and IFN-γ production...
December 4, 2018: Journal of Experimental & Clinical Cancer Research: CR
Elisabeth G Bjørnsen, Lavanya Thiruchelvam-Kyle, Sigurd E Hoelsbrekken, Camilla Henden, Per C Saether, Preben Boysen, Michael R Daws, Erik Dissen
NK cells kill cancer cells and infected cells upon activation by cell surface receptors. Human NKp30 is an activating receptor expressed by all mature NK cells. The B7 family member B7H6 has been identified as one ligand for NKp30. Several alternative ligands have also been reported, and the field remains unsettled. To this end, we have identified full-length functional B7H6 orthologs in rat and cattle, demonstrated by phylogenetic analysis and transfection experiments. In cell-cell contact-dependent assays, chimeric NKp30 reporter cells responded strongly to B7H6 in rat and cattle...
December 4, 2018: European Journal of Immunology
Xiaohong Lv, Yun Gao, Tantan Dong, Libo Yang
BACKGROUND This study investigated the distribution and features of natural killer T (NKT) cells in the peripheral blood of diabetic patients, and their regulatory roles on vascular endothelial cells. MATERIAL AND METHODS Peripheral lymphocytes were isolated from diabetic patients. NKT cell distribution, proportion, and surface and intracellular markers were detected with flow cytometry. Peripheral blood-derived NKT cells were isolated and co-cultured with human umbilical vein endothelial cells (HUVECs). Proliferation and migration of HUVECs were assessed with the CCK-8 assay and the Transwell chamber assay...
November 19, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Cordelia Manickam, Haiying Li, Spandan V Shah, Kyle Kroll, R Keith Reeves
Natural killer cells are primary immune effector cells with both innate and potentially adaptive functions against viral infections, but commonly become exhausted or dysfunctional during chronic diseases such as HIV. Chimpanzees are the closest genetic relatives of humans and have been previously used in immunology, behavior, and disease models. Due to their similarities to humans, a better understanding of chimpanzee immunology, particularly innate immune cells, can lend insight into the evolution of human immunology, as well as response to disease...
November 12, 2018: International Immunology
Xiao-Xiao Wang, Bi-Fen Luo, Han-Ji Jiang, Xu Cong, Qian Jin, Dan-Li Ma, Lai Wei, Bo Feng
AIM: To investigate how natural killer (NK) cells are affected in the elimination of hepatitis C virus (HCV) by sofosbuvir/ledipasvir, two highly effective direct-acting antivirals (DAAs). METHODS: Thirteen treatment-naïve and treatment-experienced chronic hepatitis C (CHC) patients were treated with sofosbuvir/ledipasvir, and NK cells were detected at baseline, weeks 2, 4, 8 and 12 during therapy, and week post of treatment (Pt)-12 and 24 after the end of therapy by multicolor flow cytometry and compared with those from 13 healthy controls...
October 28, 2018: World Journal of Gastroenterology: WJG
Fabio Morandi, Loredana Amoroso, Alessandra Dondero, Roberta Castriconi, Stefano Parodi, Roberto Luksch, Fiorina Casale, Aurora Castellano, Alberto Garaventa, Alessandro Moretta, Cristina Bottino, Mirco Ponzoni, Maria Valeria Corrias
Several studies support the notion that the kinase inhibitor Imatinib mesylate exerts off-target effects on cells of the immune system. After our first report of continuous daily oral administration in subjects with relapsed/refractory neuroblastoma (NB, EudraCT: 2005-005778-63), here we update the clinical information and report additional information on potential surrogate markers for prediction of efficacy. Peripheral blood (PB) samples collected at study entry and after the first and second cycle of Imatinib mesylate treatment were tested for IFN- γ , TNF-α, TGF-β, IL-10, CXCL12 and soluble (s) B7-H6 plasma levels...
2018: Oncoimmunology
Olivier Lucar, Mariama Sadjo Diallo, Charles Bayard, Assia Samri, Nadine Tarantino, Patrice Debré, Rodolphe Thiébaut, Françoise Brun-Vézinet, Sophie Matheron, Rémi Cheynier, Vincent Vieillard
OBJECTIVE: HIV-1 and HIV-2 differ notably in their epidemiology, with worldwide HIV-1 spread and HIV-2 mainly confined to West Africa. Natural killer (NK) cells are critical antiviral effectors of the immune system; however, limited information is available about these innate effector cells during HIV-2 infection. METHOD: In this study, 24 untreated HIV-2-infected patients were analyzed and compared with 21 long-term nonprogressor and 10 controller HIV-1 patients, and healthy donors...
October 15, 2018: AIDS
Martina Bonacini, Alessandra Soriano, Alessandro Zerbini, Eleonora Calò, Luca Cimino, Francesco Muratore, Luigi Fontana, Luca Braglia, Maria Parmeggiani, Carlo Salvarani, Stefania Croci
Behçet disease (BD) is an inflammatory systemic disease with a fluctuating course, which can affect the skin, eyes, central nervous system, musculoskeletal, gastrointestinal, and vascular systems. No laboratory tests are currently available for the diagnosis of BD and monitoring disease activity. Moreover there is a lack of knowledge on BD pathogenesis. This study focused on circulating Natural Killer (NK), NKT and T cells evaluated as CD3neg CD56pos , CD3pos CD56pos , and CD3pos CD56neg . Peripheral blood mononuclear cells (PBMCs) were collected from 38 BD patients and 20 healthy controls (HC)...
2018: Frontiers in Immunology
Hiroki Kabata, Kazuyo Moro, Shigeo Koyasu
Group 2 innate lymphoid cells (ILC2s) play critical roles in the induction of type 2 inflammation, response to parasite infection, metabolic homeostasis, and tissue repair. These multifunctional roles of ILC2s are tightly controlled by complex regulatory systems in the local microenvironment, the disruption of which may cause various health problems. This review summarizes up-to-date knowledge regarding positive and negative regulators for ILC2s based on their function and signaling pathways, including activating cytokines (IL-33, IL-25; MAPK, NF-κB pathways), co-stimulatory cytokines (IL-2, IL-7, IL-9, TSLP; STAT5, IL-4; STAT6, TNF superfamily; MAPK, NF-κB pathways), suppressive cytokines (type1 IFNs, IFN-γ, IL-27; STAT1, IL-10, TGF-β), transdifferentiation cytokines (IL-12; STAT4, IL-1β, IL-18), lipid mediators (LTC4, LTD4, LTE4, PGD2; Ca2+ -NFAT pathways, PGE2, PGI2; AC/cAMP/PKA pathways, LXA4, LTB4), neuropeptides (NMU; Ca2+ -NFAT, MAPK pathways, VIP, CGRP, catecholamine, acetylcholine), sex hormones (androgen, estrogen), nutrients (butyrate; HDAC inhibitors, vitamins), and cell-to-cell interactions (ICOSL-ICOS; STAT5, B7-H6-NKp30, E-cadherin-KLRG1)...
November 2018: Immunological Reviews
Bin Han, Fang-Yuan Mao, Yong-Liang Zhao, Yi-Pin Lv, Yong-Sheng Teng, Mubing Duan, Weisan Chen, Ping Cheng, Ting-Ting Wang, Zhong-Yuan Liang, Jin-Yu Zhang, Yu-Gang Liu, Gang Guo, Quan-Ming Zou, Yuan Zhuang, Liu-Sheng Peng
Natural killer (NK) cell activity is influenced by a complex integration of signaling pathways activated downstream of both activating and inhibitory surface receptors. The tumor microenvironment can suppress NK cell activity, and there is a great clinical interest in understanding whether modulating tumor-mediated NK cell suppression and/or boosting preexisting NK cell numbers in cancer patients is therapeutically viable. To this light, we characterized the surface receptor phenotypes of peripheral blood NK cells and examined their clinical relevance to human gastric cancer (GC)...
2018: Journal of Immunology Research
Gemma A Foulds, Jayakumar Vadakekolathu, Tarek M A Abdel-Fatah, Divya Nagarajan, Stephen Reeder, Catherine Johnson, Simon Hood, Paul M Moseley, Stephen Y T Chan, A Graham Pockley, Sergio Rutella, Stephanie E B McArdle
Background: Interactions between the immune system and tumors are highly reciprocal in nature, leading to speculation that tumor recurrence or therapeutic resistance could be influenced or predicted by immune events that manifest locally, but can be detected systemically. Methods: Multi-parameter flow cytometry was used to examine the percentage and phenotype of natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs), monocyte subsets and regulatory T (Treg) cells in the peripheral blood of of 85 patients with breast cancer (50 of whom were assessed before and after one cycle of anthracycline-based chemotherapy), and 23 controls...
2018: Frontiers in Immunology
Fumihiro Hirata, Kohei Ishiyama, Yuka Tanaka, Tsuyoshi Kobayashi, Masakazu Hashimoto, Yoshihiro Saeki, Nobuki Ishida, Kazuhiro Taguchi, Junko Tanaka, Koji Arihiro, Hideki Ohdan
Aim: We investigated the chemotherapy effect of resectable colorectal cancer with liver metastasis (CRLM) on the function of intrahepatic immune cells. Methods: We classified patients into adjuvant chemotherapy (bevacizumab+CapeOX) after hepatectomy group (group A) and neoadjuvant chemotherapy followed by hepatectomy group (group B), and collected peripheral blood mononuclear cells (PBMC) and liver mononuclear cells (LMNC) to ascertain phenotypic and functional differences...
September 2018: Annals of gastroenterological surgery
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