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Zhan Wang, Zenan Wang, Shu Li, Binghao Li, Lingling Sun, Hengyuan Li, Peng Lin, Shengdong Wang, Wangsiyuan Teng, Xingzhi Zhou, Zhaoming Ye
γδ T cell-based immunotherapy for osteosarcoma (OS) has shown limited success thus far. DNA-demethylating agents not only induce tumor cell death but also have an immunomodulatory function. In this study, we have assessed the potential benefit of combining decitabine (DAC, a DNA demethylation drug) and γδ T cells for OS immunotherapy. DAC increased the expression of natural killer group 2D (NKG2D) ligands (NKG2DLs), including major histocompatibility complex class I-related chains B (MICB) and UL16-binding protein 1 (ULBP1), on the OS cell surface, making the cells more sensitive to recognition and destruction by cytotoxic γδ T cells...
2018: Frontiers in Immunology
Marina Babic, Chiara Romagnani
Current medicine and medical science puts great effort into elucidating the basis of chronicity and finding appropriate treatments for inflammatory diseases; however, the mechanisms driving aberrant immune responses are mostly unknown and deserve further study. Of particular interest is the identification of checkpoints that regulate the function and differentiation of pro-inflammatory cells during pathogenesis, along with means of their modulation for therapeutic purposes. Natural killer group 2, member D (NKG2D) is a potent activator of the immune system, known as a sensor for "induced-self" ligands, i...
2018: Frontiers in Immunology
Delfina Costa, Roberta Venè, Roberto Benelli, Emanuele Romairone, Stefano Scabini, Silvia Catellani, Barbara Rebesco, Luca Mastracci, Federica Grillo, Simona Minghelli, Fabrizio Loiacono, Maria Raffaella Zocchi, Alessandro Poggi
Mesenchymal stromal cells (MSC) present in the tumor microenvironment [usually named tumor-associated fibroblasts (TAF)] can exert immunosuppressive effects on T and natural killer (NK) lymphocytes, favoring tumor immune escape. We have analyzed this mechanism in colorectal carcinoma (CRC) and found that co-culture of NK cells with TAF can prevent the IL-2-mediated NKG2D upregulation. This leads to the impairment of NKG2D-mediated recognition of CRC cells, sparing the NK cell activation through DNAM1 or FcγRIIIA (CD16)...
2018: Frontiers in Immunology
Alex M Abel, Aradhana A Tiwari, Zachary J Gerbec, Jason R Siebert, Chao Yang, Nathan J Schloemer, Kate J Dixon, Monica S Thakar, Subramaniam Malarkannan
Natural killer (NK) cells are innate lymphocytes that play essential roles in mediating antitumor immunity. NK cells respond to various inflammatory stimuli including cytokines and stress-induced cellular ligands which activate germline-encoded activation receptors (NKRs), such as NKG2D. The signaling molecules activated downstream of NKRs are well defined; however, the mechanisms that regulate these pathways are not fully understood. IQ domain-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffold protein...
2018: Frontiers in Immunology
Dina Al Dulaimi, Jihene Klibi, Veronica Olivo Pimentel, Veronique Parietti, Matthieu Allez, Antoine Toubert, Kamel Benlagha
Natural killer group 2D (NKG2D) is a well-characterized activating receptor expressed on many immune cells, including invariant natural killer T (iNKT) cells. These cells were shown to be responsible of liver injury in the model of concanavalin A (Con A)-induced hepatitis, considered to be an experimental model of human autoimmune hepatitis. In this study, we investigated whether NKG2D plays a role in the hepatitis induced by iNKT cell-mediated immune response to Con A. By using killer cell lectin-like receptor subfamily K, member 1 deficient ( Klrk1 -/- ) mice, we found that the absence of NKG2D reduced the hepatic injury upon Con A administration...
2018: Frontiers in Immunology
Nicholas J W Easom, Kerstin A Stegmann, Leo Swadling, Laura J Pallett, Alice R Burton, Dennis Odera, Nathalie Schmidt, Wei-Chen Huang, Giuseppe Fusai, Brian Davidson, Mala K Maini
NK cells have potent antitumor capacity. They are enriched in the human liver, with a large subset specialized for tissue-residence. The potential for liver-resident versus liver-infiltrating NK cells to populate, and exert antitumor functions in, human liver tumors has not been studied. We examined liver-resident and liver-infiltrating NK cells directly ex vivo from human hepatocellular carcinomas (HCCs) and liver colorectal (CRC) metastases, compared with matched uninvolved liver tissue. We found that NK cells were highly prevalent in both HCC and liver CRC metastases, although at lower frequencies than unaffected liver...
2018: Frontiers in Immunology
Lea Hiršl, Ilija Brizić, Tina Jenuš, Vanda Juranić Lisnić, Johanna Julia Reichel, Slaven Jurković, Astrid Krmpotić, Stipan Jonjić
The development of a vaccine against human cytomegalovirus (CMV) has been a subject of long-term medical interest. The research during recent years identified CMV as an attractive vaccine vector against infectious diseases and tumors. The immune response to CMV persists over a lifetime and its unique feature is the inflationary T cell response to certain viral epitopes. CMV encodes numerous genes involved in immunoevasion, which are non-essential for virus growth in vitro . The deletion of those genes results in virus attenuation in vivo , which enables us to dramatically manipulate its virulence and the immune response...
2018: Frontiers in Immunology
Vito Pistoia, Nicola Tumino, Paola Vacca, Irene Veneziani, Alessandro Moretta, Franco Locatelli, Lorenzo Moretta
γδ T lymphocytes are potent effector cells, capable of efficiently killing tumor and leukemia cells. Their activation is mediated by γδ T-cell receptor (TCR) and by activating receptors shared with NK cells (e.g., NKG2D and DNAM-1). γδ T-cell triggering occurs upon interaction with specific ligands, including phosphoantigens (for Vγ9Vδ2 TCR), MICA-B and UL16 binding protein (for NKG2D), and PVR and Nectin-2 (for DNAM-1). They also respond to cytokines undergoing proliferation and release of cytokines/chemokines...
2018: Frontiers in Immunology
Hana Rohn, Rafael Tomoya Michita, Esther Schwich, Sebastian Dolff, Anja Gäckler, Mirko Trilling, Vu Thuy Khanh Le-Trilling, Benjamin Wilde, Johannes Korth, Falko M Heinemann, Peter A Horn, Andreas Kribben, Oliver Witzke, Vera Rebmann
The interaction of major histocompatibility complex class I chain-related protein A (MICA) and its cognate activating receptor natural killer (NK) group 2 member D (NKG2D) receptor plays a significant role in viral immune control. In the context of kidney transplantation (KTx), cytomegalovirus (CMV) frequently causes severe complications. Hypothesizing that functional polymorphisms of the MICA/NKG2D axis might affect antiviral NK and T cell responses to CMV, we explored the association of the MICA-129 Met/Val single nucleotide polymorphism (SNP) (affecting the binding affinity of MICA with the NKG2D receptor), the MICA rs2596538 G/A SNP (influencing MICA transcription), and the NKG2D rs1049174 G/C SNP (determining the cytotoxic potential of effector cells) with the clinical outcome of CMV during the first year after KTx in a cohort of 181 kidney donor-recipients pairs...
2018: Frontiers in Immunology
Peter J Darlington, Brandon Stopnicki, Tarik Touil, Jean-Sebastien Doucet, Lama Fawaz, Morgan E Roberts, Marie-Noëlle Boivin, Nathalie Arbour, Mark S Freedman, Harold L Atkins, Amit Bar-Or
In autoimmunity, the balance of different helper T (Th) cell subsets can influence the tissue damage caused by autoreactive T cells. Pro-inflammatory Th1 and Th17 T cells are implicated as mediators of several human autoimmune conditions such as multiple sclerosis (MS). Autologous hematopoietic stem cell transplantation (aHSCT) has been tested in phase 2 clinical trials for MS patients with aggressive disease. Abrogation of new clinical relapses and brain lesions can be seen after ablative aHSCT, accompanied by significant reductions in Th17, but not Th1, cell populations and activity...
2018: Frontiers in Immunology
Zhijie Lin, Sen Han, Xingxing Qian, Chunxia Hu, Weiming Xiao, Li Qian, Yu Zhang, Yanbing Ding, Xiaoqin Jia, Guoqiang Zhu, Weijuan Gong
Regulatory T cells play critical roles in self-tolerance and tumor evasion. CD4+ NKG2D+ cells with regulatory activity are present in patients with NKG2DL+ tumors and juvenile systemic lupus erythematosus. We previously showed that TGF-β-producing CD4+ NKG2D+ T cells are present in pCD86-Rae-1ε transgenic mice. Here, we performed both ex vivo and in vivo studies on pCD86-Rae-1ε transgenic mice and an MC38 tumor-bearing mouse model and show that NK1.1- CD4+ NKG2D+ T cells have regulatory activity in pCD86-Rae-1ε transgenic mice...
May 25, 2018: Cancer Immunology, Immunotherapy: CII
F Rajabi, L A Drake, M M Senna, N Rezaei
Alopecia areata is a disorder that results in non-scarring hair loss. The psychological impact can be significant, leading to feelings of depression and social isolation. The disease remains incurable though it has been studied for years. Available treatment options at best, are beneficial for milder cases, and the rate of relapse is high. Understanding the exact mechanisms of hair loss in alopecia areata is therefore of utmost importance to help identify potential therapeutic targets. The main theory of alopecia areata pathogenesis is that it is an autoimmune phenomenon resulting from a disruption in hair follicle immune privilege...
May 23, 2018: British Journal of Dermatology
Chun Xu, Xian Lu, Wei Liu, Anxian Chen, Gang Meng, Hailin Zhang, Binghua Li, Yonghui Zhang, Junhua Wu, Jiwu Wei
BACKGROUND: Tumor-promoting inflammation is an emerging hallmark of cancer, which participates in both cancer progression and immune escape. Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer with an extremely poor prognosis. Frankincense and myrrh are anti-inflammation agents commonly used in clinic. The purpose of this study is to investigate whether extract of frankincense and myrrh (FM) downregulates inflammatory microenvironment of HCC and thereby restores antitumor immune responses...
May 21, 2018: Journal of Translational Medicine
Wing Keung Chan, Siwen Kang, Youssef Youssef, Erin N Glankler, Emma R Barrett, Alex M Carter, Elshafa H Ahmed, Aman Prasad, Luxi Chen, Jianying Zhang, Don M Benson, Michael A Caligiuri, Jianhua Yu
Multiple myeloma (MM) is an incurable hematological malignancy of plasma cells with an estimated 30,000 new cases diagnosed each year in the United States, signifying the need for new therapeutic approaches. We hypothesized that targeting MM using a bispecific antibody (biAb) to simultaneously engage both innate and adaptive cytolytic immune cells could present potent antitumor activity. We engineered a biAb by fusing an anti-CS1 single chain variable fragment (scFv) and an anti-NKG2D scFv (CS1-NKG2D biAb)...
May 16, 2018: Cancer Immunology Research
Alessandra Zingoni, Elisabetta Vulpis, Francesca Cecere, Maria G Amendola, Daniel Fuerst, Taron Saribekyan, Adnane Achour, Tatyana Sandalova, Ilaria Nardone, Agnese Peri, Alessandra Soriani, Cinzia Fionda, Elena Mariggiò, Maria T Petrucci, Maria R Ricciardi, Joannis Mytilineos, Marco Cippitelli, Cristina Cerboni, Angela Santoni
Natural killer (NK) cells are immune innate effectors playing a pivotal role in the immunosurveillance of multiple myeloma (MM) since they are able to directly recognize and kill MM cells. In this regard, among activating receptors expressed by NK cells, NKG2D represents an important receptor for the recognition of MM cells, being its ligands expressed by tumor cells, and being able to trigger NK cell cytotoxicity. The MHC class I-related molecule A (MICA) is one of the NKG2D ligands; it is encoded by highly polymorphic genes and exists as membrane-bound and soluble isoforms...
2018: Frontiers in Immunology
Antonino Bruno, Barbara Bassani, Davide Giuseppe D'Urso, Ilvana Pitaku, Elisa Cassinotti, Giuseppe Pelosi, Luigi Boni, Lorenzo Dominioni, Douglas M Noonan, Lorenzo Mortara, Adriana Albini
NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solid malignancies, NK cells have compromised functions. We have previously reported that lung tumor-associated NK cells (TANKs; peripheral blood) and tumor-infiltrating NK cells (TINKs) show proangiogenic, decidual NK-like (dNK) phenotype. In this study, we functionally and molecularly investigated TINKs and TANKs from blood and tissue samples of patients with colorectal cancer (CRC), a neoplasm in which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease...
May 15, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Thornton W Thompson, Benjamin T Jackson, P Jonathan Li, Jiaxi Wang, Alexander Byungsuk Kim, Kristen Ting Hui Huang, Lily Zhang, David H Raulet
NKG2D is an important immunoreceptor expressed on the surface of NK cells and some T cells. NKG2D recognizes a set of ligands typically expressed on infected or transformed cells, but recent studies have also documented NKG2D ligands on subsets of host non-tumor cells in tumor-bearing animals and humans. Here we show that in transplanted tumors and genetically engineered mouse cancer models, tumor-associated macrophages are induced to express the NKG2D ligand RAE-1δ. We find that a soluble factor produced by tumor cells is responsible for macrophage RAE-1δ induction, and we identify tumor-derived colony-stimulating factor-1 (CSF-1) as necessary and sufficient for macrophage RAE-1δ induction in vitro and in vivo ...
May 14, 2018: ELife
Soo-Hyeon Lee, Dong-Jun Shin, Yoseop Kim, Cheol-Jung Kim, Je-Jung Lee, Mee Sun Yoon, Tung Nguyen Thanh Uong, Dohyeon Yu, Ji-Youn Jung, Duck Cho, Bock-Gie Jung, Sang-Ki Kim, Guk-Hyun Suh
Natural killer (NK) cells play a pivotal role in the immune response against infections and malignant transformation, and adopted transfer of NK cells is thought to be a promising therapeutic approach for cancer patients. Previous reports describing the phenotypic features of canine NK cells have produced inconsistent results. Canine NK cells are still defined as non-B and non-T (CD3- CD21- ) large granular lymphocytes. However, a few reports have demonstrated that canine NK cells share the phenotypic characteristics of T lymphocytes, and that CD3+ CD5dim CD21- lymphocytes are putative canine NK cells...
2018: Frontiers in Immunology
Leticia Huergo Zapico, Monica Parodi, Claudia Cantoni, Chiara Lavarello, Juan L Fernández-Martínez, Andrea Petretto, Enrique J DeAndrés-Galiana, Mirna Balsamo, Alejandro López-Soto, Gabriella Pietra, Mattia Bugatti, Enrico Munari, Marcella Marconi, Maria Cristina Mingari, William Vermi, Lorenzo Moretta, Segundo Gonzalez, Massimo Vitale
Tumor cell plasticity is a major obstacle for the cure of malignancies as it makes tumor cells highly adaptable to micro-environmental changes, enables their phenotype switching among different forms, and favors the generation of pro-metastatic tumor cell subsets. Phenotype switching towards more aggressive forms involves different functional, phenotypic and morphologic changes, which are often related to the process known as Epithelial-Mesenchymal Transition (EMT). In this study, we report NK cells may increase the malignancy of melanoma cells by inducing changes relevant to EMT and, more broadly, to phenotype switching from proliferative to invasive forms...
May 11, 2018: Cancer Research
Mingjing Shen, Yongbing Chen, Lijun Xu, Rongying Zhu, Xiang Xue, Ying Tsai, Peter C Keng, Soo Ok Lee, Yuhchyau Chen
In this study, in order to investigate the effects of increased macrophage infiltration to radioresistant lung tumors in regulating natural killer (NK) cell-mediated immunity, we examined whether the treatment of radioresistant cells with conditioned medium (CM) from phorbol myristate acetate (PMA)/interleukin (IL)-4 treated THP-1 cells (used as a tumor-associated macrophage source) leads to the development of the additional resistance of tumor cells to NK cell cytotoxicity. We found that the susceptibility of THP-1 CM-treated radioresistant cells to NK cell cytotoxicity was decreased compared to the non-treated cells...
July 2018: International Journal of Oncology
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