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https://www.readbyqxmd.com/read/28818060/rna-transfection-of-%C3%AE-%C3%AE-t-cells-with-a-chimeric-antigen-receptor-or-an-%C3%AE-%C3%AE-t-cell-receptor-a-safer-alternative-to-genetically-engineered-%C3%AE-%C3%AE-t-cells-for-the-immunotherapy-of-melanoma
#1
Dennis C Harrer, Bianca Simon, Shin-Ichiro Fujii, Kanako Shimizu, Ugur Uslu, Gerold Schuler, Kerstin F Gerer, Stefanie Hoyer, Jan Dörrie, Niels Schaft
BACKGROUND: Adoptive T-cell therapy relying on conventional T cells transduced with T-cell receptors (TCRs) or chimeric antigen receptors (CARs) has caused substantial tumor regression in several clinical trials. However, genetically engineered T cells have been associated with serious side-effects due to off-target toxicities and massive cytokine release. To obviate these concerns, we established a protocol adaptable to GMP to expand and transiently transfect γ/δ T cells with mRNA...
August 17, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28817117/increased-tumor-infiltrating-cd45ra-ccr7-regulatory-t-cell-subset-with-immunosuppressive-properties-foster-gastric-cancer-progress
#2
Fang-Yuan Mao, Hui Kong, Yong-Liang Zhao, Liu-Sheng Peng, Weisan Chen, Jin-Yu Zhang, Ping Cheng, Ting-Ting Wang, Yi-Pin Lv, Yong-Sheng Teng, Xiao-Long Fu, Yu-Gang Liu, Xiao-Long Wu, Chuan-Jie Hao, Nan You, Ping Luo, Pei-Wu Yu, Quan-Ming Zou, Gang Guo, Yuan Zhuang
Regulatory T cells (Tregs) are major components of tumor-infiltrating immune cells with potent immunosuppressive properties in gastric cancer (GC) microenvironment. However, different subsets of the Tregs and their relevance to GC are unknown. Here, we found that patients with GC showed a significantly higher Tregs infiltration in tumors, and CD45RA(-)CCR7(-) Treg subset constituted most tumor-infiltrating Tregs. Tumor-infiltrating CD45RA(-)CCR7(-) Treg subset with an effector/memory phenotype accumulated in tumors and expressed low level of HLA-DR...
August 17, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28815885/novel-landscape-of-hla-g-isoforms-expressed-in-clear-cell-renal-cell-carcinoma-patients
#3
Diana Tronik-Le Roux, Julie Renard, Jérôme Vérine, Victor Renault, Emmanuel Tubacher, Joel LeMaoult, Nathalie Rouas-Freiss, Jean-François Deleuze, François Desgrandschamps, Edgardo D Carosella
Immune-checkpoints are powerful inhibitory molecules that promote tumor survival. Their blockade is now recognized as providing effective therapeutic benefit against cancer. HLA-G, a recently identified immune checkpoint, has been detected in many types of primary tumors and metastases, in malignant effusions as well as on tumor-infiltrating cells, particularly in patients with clear cell renal cell carcinoma (ccRCC). Here, in order to define a possible anti-cancer therapy, we used a molecular approach based on an unbiased strategy that combines transcriptome determination and immunohistochemical labeling, to analyze in-depth, the HLA-G isoforms expressed in these tumors...
August 16, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28811976/long-lived-pancreatic-ductal-adenocarcinoma-slice-cultures-enable-precise-study-of-the-immune-microenvironment
#4
Xiuyun Jiang, Y David Seo, Jae Hyuck Chang, Andrew Coveler, Eslam N Nigjeh, Sheng Pan, Florencia Jalikis, Raymond S Yeung, Ian N Crispe, Venu G Pillarisetty
Pancreatic ductal adenocarcinoma (PDA) remains a deadly disease that is rarely cured, despite many recent successes with immunotherapy for other malignancies. As the human disease is heavily infiltrated by effector T cells, we postulated that accurately modeling the PDA immune microenvironment would allow us to study mechanisms of immunosuppression that could be overcome for therapeutic benefit. Using viable precision-cut slices from fresh PDA, we developed an organotypic culture system for this purpose. We confirmed that cultured slices maintain their baseline morphology, surface area, and microenvironment after at least 6 d in culture, and demonstrated slice survival by MTT assay and by immunohistochemistry staining with Ki-67 and cleaved-Caspase-3 antibodies...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28807769/reduced-intensity-haploidentical-bone-marrow-transplantation-with-post-transplant-cyclophosphamide-for-solid-tumors-in-pediatric-and-young-adult-patients
#5
Nicolas J Llosa, Kenneth R Cooke, Allen Chen, Christopher Gamper, Orly Klein, Elias Zambidis, Brandon Luber, Gary Rosner, Nicholas Siegel, Mary Jo Holuba, Nancy Robey, Masanori Hayashi, Richard J Jones, Ephraim Fuchs, Matthias Holdhoff, David M Loeb, Heather J Symons
High risk, recurrent, or refractory solid tumors in pediatric, adolescent and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant (alloBMT) platform using a reduced intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received a fludarabine, cyclophosphamide (Cy), melphalan and low dose total body irradiation (TBI) RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil (MMF) and sirolimus...
August 11, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28807569/il-10-engineered-human-cd4-tr1-cells-eliminate-myeloid-leukemia-in-an-hla-class-i-dependent-mechanism
#6
Grazia Locafaro, Grazia Andolfi, Fabio Russo, Luca Cesana, Antonello Spinelli, Barbara Camisa, Fabio Ciceri, Angelo Lombardo, Attilio Bondanza, Maria Grazia Roncarolo, Silvia Gregori
T regulatory cells (Tregs) play a key role in modulating T cell responses. Clinical trials showed that Tregs modulate graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, their ability to mediate anti-leukemic activity (graft-versus-leukemia [GvL]) is largely unknown. Enforced interleukin-10 (IL-10) expression converts human CD4(+) T cells into T regulatory type 1 (Tr1)-like (CD4(IL-10)) cells that suppress effector T cells in vitro and xenoGvHD in humanized mouse models...
July 5, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28806729/erk2-and-jnk1-contribute-to-tnf-%C3%AE-induced-il-8-expression-in-synovial-fibroblasts
#7
Shinichi Namba, Rei Nakano, Taku Kitanaka, Nanako Kitanaka, Tomohiro Nakayama, Hiroshi Sugiya
Tumor necrosis factor α (TNF-α) induces the expression and secretion of interleukin 8 (IL-8), which contributes to synovitis in rheumatoid arthritis (RA). To elucidate the mechanism of the onset of RA, we used synovial fibroblasts without autoimmune inflammatory diseases and investigated MAPK signaling pathways in TNF-α-induced IL-8 expression. Synovial fibroblasts isolated from healthy dogs were characterized by flow cytometry, which were positive for the fibroblast markers CD29, CD44, and CD90 but negative for the hematopoietic cell markers CD14, CD34, CD45, and HLA-DR...
2017: PloS One
https://www.readbyqxmd.com/read/28802832/retroviral-gene-transfer-into-primary-human-nk-cells-activated-by-il-2-and-k562-feeder-cells-expressing-membrane-bound-il-21
#8
Maria A Streltsova, Eugene Barsov, Sofia A Erokhina, Elena I Kovalenko
Natural killer (NK) cells are capable of rapidly recognizing and efficiently killing tumor cells. This makes them a potentially promising agent for cancer immunotherapy. Additional genetic modifications of NK cells may further improve their anti-tumor efficacy. Numerous technical challenges associated with gene delivery into NK cells have significantly tempered this approach. We achieved efficient retroviral vector transduction of primary human NK cells that were stimulated by a combination of IL-2 and engineered K562 cells expressing membrane-bound IL-21...
August 9, 2017: Journal of Immunological Methods
https://www.readbyqxmd.com/read/28792537/isolation-and-functional-characterization-of-hepatitis-b-virus-specific-t-cell-receptors-as-new-tools-for-experimental-and-clinical-use
#9
Karin Wisskirchen, Kai Metzger, Sophia Schreiber, Theresa Asen, Luise Weigand, Christina Dargel, Klaus Witter, Elisa Kieback, Martin F Sprinzl, Wolfgang Uckert, Matthias Schiemann, Dirk H Busch, Angela M Krackhardt, Ulrike Protzer
T-cell therapy of chronic hepatitis B is a novel approach to restore antiviral T-cell immunity and cure the infection. We aimed at identifying T-cell receptors (TCR) with high functional avidity that have the potential to be used for adoptive T-cell therapy. To this end, we cloned HLA-A*02-restricted, hepatitis B virus (HBV)-specific T cells from patients with acute or resolved HBV infection. We isolated 11 envelope- or core-specific TCRs and evaluated them in comprehensive functional analyses. T cells were genetically modified by retroviral transduction to express HBV-specific TCRs...
2017: PloS One
https://www.readbyqxmd.com/read/28781970/hypoxic-modulation-of-hla-g-expression-through-the-metabolic-sensor-hif-1-in-human-cancer-cells
#10
REVIEW
Marica Garziera, Lucia Scarabel, Giuseppe Toffoli
The human leukocyte antigen-G (HLA-G) is considered an immune checkpoint molecule involved in tumor immune evasion. Hypoxia and the metabolic sensor hypoxia-inducible factor 1 (HIF-1) are hallmarks of metastasization, angiogenesis, and intense tumor metabolic activity. The purpose of this review was to examine original in vitro studies carried out in human cancer cell lines, which reported data about HLA-G expression and HIF-1 mediated-HLA-G expression in response to hypoxia. The impact of HLA-G genomic variability on the hypoxia responsive elements (HREs) specific for HIF-1 binding was also discussed...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28776578/negative-immune-checkpoint-regulation-by-vista-a-mechanism-of-acquired-resistance-to-anti-pd-1-therapy-in-metastatic-melanoma-patients
#11
Hojabr Kakavand, Louise A Jackett, Alexander M Menzies, Tuba N Gide, Matteo S Carlino, Robyn P M Saw, John F Thompson, James S Wilmott, Georgina V Long, Richard A Scolyer
Understanding the mechanisms of acquired resistance to anti-PD-1 will allow development of better treatment strategies for cancer patients. This study evaluated potential mechanisms of acquired resistance to anti-PD-1 in longitudinally collected metastatic melanoma patient biopsies. Thirty-four metastatic melanoma biopsies were collected from 16 patients who had initially responded to either anti-PD-1 (n=13) alone or combination of anti-PD-1 and ipilimumab (n=3) and then progressed. Biopsies were taken prior to treatment (PRE, n=12) and following progression of disease (PROG, n=22)...
August 4, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28775208/a-multikinase-and-dna-pk-inhibitor-combination-immunomodulates-melanomas-suppresses-tumor-progression-and-enhances-immunotherapies
#12
Alexander K Tsai, Asra Y Khan, Christina E Worgo, Lucy L Wang, Yuanyuan Liang, Eduardo Davila
Combination therapies have the potential to improve outcomes in melanoma patients but have not yet been clinically efficacious. Here, we used high-throughput flow cytometry-based screening to identify and characterize candidate therapies that might synergize with and augment T-cell immunotherapy efficacy. Two lead therapies, regorafenib and NU7441, were selected based on their ability to alter a variety of immunomodulatory proteins, including CD55, CD73, CD155, programmed death-ligand 1 (PD-L1), nerve growth factor receptor (NGFR), and HLA class I in a heterogeneous panel of melanomas...
August 3, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28771573/human-leucocyte-antigen-hla-dr-gene-expression-is-reduced-in-sepsis-and-correlates-with-impaired-tnf%C3%AE-response-a-diagnostic-tool-for-immunosuppression
#13
Martin Sebastian Winkler, Anne Rissiek, Marion Priefler, Edzard Schwedhelm, Linda Robbe, Antonia Bauer, Corinne Zahrte, Christian Zoellner, Stefan Kluge, Axel Nierhaus
BACKGROUND: Sepsis is defined as a dysregulated immune response to infection. Impaired immune response in sepsis, often described as endotoxin tolerance, is characterized by unresponsiveness of monocytes on lipopolysaccharide (LPS) stimulation to release tumor necrosis factor α (TNFα). Furthermore, decreased monocyte surface protein expression of human leucocyte antigen DR (HLA-DR) is a marker for changes of the innate immune response during sepsis. Quantitative polymerase chain reaction (qPCR) and flow-cytometry (FACS) have been used to measure protein or gene expression of HLA-DR...
2017: PloS One
https://www.readbyqxmd.com/read/28771191/somatic-host-cell-alterations-in-hpv-carcinogenesis
#14
REVIEW
Tamara R Litwin, Megan A Clarke, Michael Dean, Nicolas Wentzensen
High-risk human papilloma virus (HPV) infections cause cancers in different organ sites, most commonly cervical and head and neck cancers. While carcinogenesis is initiated by two viral oncoproteins, E6 and E7, increasing evidence shows the importance of specific somatic events in host cells for malignant transformation. HPV-driven cancers share characteristic somatic changes, including apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)-driven mutations and genomic instability leading to copy number variations and large chromosomal rearrangements...
August 3, 2017: Viruses
https://www.readbyqxmd.com/read/28761441/association-between-hla-dq-gene-polymorphisms-and-hbv-related-hepatocellular-carcinoma
#15
REVIEW
Jingzhu Lv, Tao Xu, Zhongqing Qian, Hongtao Wang
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality worldwide. Host gene variants may influence hepatitis B virus- (HBV-) related HCC. Human leukocyte antigens (HLA) play an important role in presenting virus antigens to immune cells that are responsible for the clearance of virus-infected cells and tumor cells. Previous studies have investigated the HLA-DQ (rs2856718 and rs9275572) polymorphisms that may be associated with the development of HBV-related HCC. However, the results are controversial or inconclusive...
2017: Gastroenterology Research and Practice
https://www.readbyqxmd.com/read/28754545/major-histocompatibility-mismatch-and-donor-choice-for-second-allogeneic-bone-marrow-transplant
#16
Philip H Imus, Amanda L Blackford, Maria Bettinotti, Brian Iglehart, August Dietrich, Noah Tucker, Heather Symons, Kenneth R Cooke, Leo Luznik, Ephraim J Fuchs, Robert A Brodsky, William H Matsui, Carol Ann Huff, Douglas Gladstone, Richard F Ambinder, Ivan M Borrello, Lode J Swinnen, Richard J Jones, Javier Bolaños-Meade
Large alternative donor pools provide the potential for selecting a different donor for a second allogeneic transplant (alloBMT). As HLA disparity may contribute to the graft versus tumor effect, potentially utilizing new mismatched haplotype donors could improve the antitumor activity for relapsed hematologic malignancies despite a previous alloBMT. Data from patients who received a second alloBMT for relapsed hematologic malignancies at Johns Hopkins were analyzed. Outcomes were compared between patients who received a second allograft with the same MHC composition and those who received an allograft with a new mismatched haplotype...
July 25, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28749573/il-6-stat3-signaling-as-a-promising-target-to-improve-the-efficacy-of-cancer-immunotherapy
#17
REVIEW
Hidemitsu Kitamura, Yosuke Ohno, Yujiro Toyoshima, Junya Ohtake, Shigenori Homma, Hideki Kawamura, Norihiko Takahashi, Akinobu Taketomi
Overcoming the immunosuppressive state in tumor microenvironments is a critical issue to improve the efficacy of cancer immunotherapy. Interleukin (IL)-6, a pleiotropic cytokine, is highly produced in the tumor-bearing host. Previous studies have indicated that IL-6 suppresses the antigen presentation ability of dendritic cells (DCs) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL-6/STAT3 signaling cascade on human DCs and the subsequent induction of antitumor T cell immune responses...
July 27, 2017: Cancer Science
https://www.readbyqxmd.com/read/28740236/reduced-expression-of-the-murine-hla-g-homolog-qa-2-is-associated-with-malignancy-epithelial-mesenchymal-transition-and-stemness-in-breast-cancer-cells
#18
Istéfani L da Silva, Lucía Montero-Montero, Ester Martín-Villar, Jorge Martin-Pérez, Bruno Sainz, Jaime Renart, Renata Toscano Simões, Émerson Soares Veloso, Cláudia Salviano Teixeira, Mônica C de Oliveira, Enio Ferreira, Miguel Quintanilla
Qa-2 is believed to mediate a protective immune response against cancer; however, little is known about the role of Qa-2 in tumorigenesis. Here, we used 4T1 breast cancer cells to study the involvement of Qa-2 in tumor progression in a syngeneic host. Qa-2 expression was reduced during in vivo tumor growth and in cell lines derived from 4T1-induced tumors. Tumor-derived cells elicited an epithelial-mesenchymal transition associated with upregulation of Zeb1 and Twist1/2 and enhanced tumor initiating and invasive capacities...
July 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28739030/immune-modulatory-micrornas-as-a-novel-mechanism-to-revert-immune-escape-of-tumors
#19
REVIEW
Barbara Seliger
Tumors have developed different strategies to escape immune recognition. This could be due to altered expression of classical and non-classical human leukocyte antigens (HLA), co-inhibitory or co-stimulatory molecules as well as components of the interferon signaling pathway. Furthermore, changes in the tumor microenvironment negatively interfere with anti-tumor immune responses and the frequency and activity of immune effector cells and professional antigen presenting cells (APC), while the number of immune suppressive cells is increased...
July 13, 2017: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/28736223/semaphorin-3a-in-ankylosing-spondylitis
#20
Hsien-Tzung Liao, Yuh-Feng Lin, Chung-Tei Chou, Chang-Youh Tsai
BACKGROUND/PURPOSE: To determine serum semaphorin 3A (Sema 3A) levels in ankylosing spondylitis (AS). METHODS: Serum Sema 3A was measured in 46 AS patients and 30 healthy controls (HCs). For the patients, we recorded demographic data, disease activity, functional index & global assessment, detected human leukocyte antigen-B27 (HLA-B27), and measured erythrocyte sedimentation rate (ESR) & C-reactive protein (CRP). RESULTS: Sema 3A was higher in AS patients than in HCs (3...
July 14, 2017: Journal of Microbiology, Immunology, and Infection, Wei Mian Yu Gan Ran za Zhi
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