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TCR Immunotherapy

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https://www.readbyqxmd.com/read/30111633/human-lymph-nodes-maintain-tcf-1-hi-memory-t-cells-with-high-functional-potential-and-clonal-diversity-throughout-life
#1
Michelle Miron, Brahma V Kumar, Wenzhao Meng, Tomer Granot, Dustin J Carpenter, Takashi Senda, Dora Chen, Aaron M Rosenfeld, Bochao Zhang, Harvey Lerner, Amy L Friedman, Uri Hershberg, Yufeng Shen, Adeeb Rahman, Eline T Luning Prak, Donna L Farber
Translating studies on T cell function and modulation from mouse models to humans requires extrapolating in vivo results on mouse T cell responses in lymphoid organs (spleen and lymph nodes [LN]) to human peripheral blood T cells. However, our understanding of T cell responses in human lymphoid sites and their relation to peripheral blood remains sparse. In this study, we used a unique human tissue resource to study human T cells in different anatomical compartments within individual donors and identify a subset of memory CD8+ T cells in LN, which maintain a distinct differentiation and functional profile compared with memory CD8+ T cells in blood, spleen, bone marrow, and lungs...
August 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/30104252/cd19-alterations-emerging-after-cd19-directed-immunotherapy-cause-retention-of-the-misfolded-protein-in-the-endoplasmic-reticulum
#2
Asen Bagashev, Elena Sotillo, Chih-Hang Anthony Tang, Kathryn L Black, Jessica Perazzelli, Steven H Seeholzer, Yair Argon, David M Barrett, Stephan A Grupp, Chih-Chi Andrew Hu, Andrei Thomas-Tikhonenko
We have previously described a mechanism of acquired resistance of B-cell acute lymphoblastic leukemia to CD19-directed chimeric antigen receptor T-cell (CART) immunotherapy. It was based on in-frame insertions in or skipping of CD19 exon 2. To distinguish between epitope loss and defects in surface localization, we used retroviral transduction and genome editing to generate cell lines expressing CD19 exon 2 variants (CD19ex2vs) bearing VSV-G tags. These lines were negative by live-cell flow cytometry with an anti-VSV-G antibody and resistant to killing by VSV-G directed antibody-drug conjugates (ADC), suggestive of a defect in surface localization...
August 13, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/30103488/the-generation-of-car-transfected-natural-killer-t-cells-for-the-immunotherapy-of-melanoma
#3
Bianca Simon, Manuel Wiesinger, Johannes März, Kilian Wistuba-Hamprecht, Benjamin Weide, Beatrice Schuler-Thurner, Gerold Schuler, Jan Dörrie, Ugur Uslu
Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR...
August 11, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/30076771/from-stability-to-dynamics-understanding-molecular-mechanisms-of-regulatory-t-cells-through-foxp3-transcriptional-dynamics
#4
REVIEW
David Bending, Masahiro Ono
Studies on regulatory T cells (Treg) have focused on thymic Treg as a stable lineage of immunosuppressive T cells, the differentiation of which is controlled by the transcription factor Foxp3. This lineage perspective, however, may constrain hypotheses regarding the role of Foxp3 and Treg in vivo, particularly in clinical settings and immunotherapy development. In this review, we synthesise a new perspective on the role of Foxp3 as a dynamically expressed gene, and thereby revisit the molecular mechanisms for the transcriptional regulation of Foxp3...
August 4, 2018: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/30065096/regulatory-t-cells-in-ovarian-cancer-are-characterized-by-a-highly-activated-phenotype-distinct-from-that-in-melanoma
#5
Aras Toker, Linh T Nguyen, Simone C Stone, Cindy Yang, Sarah R Katz, Patricia A Shaw, Blaise A Clarke, Danny A Ghazarian, Ayman S Al Habeeb, Alexandra M Easson, Wey Leong, David McCready, Michael Reedijk, Cynthia J Guidos, Trevor J Pugh, Marcus Q Bernardini, Pamela S Ohashi
PURPOSE: Regulatory T (Treg) cells expressing the transcription factor FOXP3 are essential for the maintenance of immunological self-tolerance but play a detrimental role in most cancers due to their ability to suppress antitumor immunity. The phenotype of human circulating Treg cells has been extensively studied, but less is known about tumor-infiltrating Treg cells. We studied the phenotype and function of tumor-infiltrating Treg cells in ovarian cancer and melanoma to identify potential Treg cell-associated molecules that can be targeted by tumor immunotherapies...
July 31, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30060805/%C3%AE-%C3%AE-t-cell-receptor-mechanosensing-forces-out-serial-engagement
#6
REVIEW
Yinnian Feng, Ellis L Reinherz, Matthew J Lang
T lymphocytes use αβ T cell receptors (TCRs) to recognize sparse antigenic peptides bound to MHC molecules (pMHCs) arrayed on antigen-presenting cells (APCs). Contrary to conventional receptor-ligand associations exemplified by antigen-antibody interactions, forces play a crucial role in nonequilibrium mechanosensor-based T cell activation. Both T cell motility and local cytoskeleton machinery exert forces (i.e., generate loads) on TCR-pMHC bonds. We review biological features of the load-dependent activation process as revealed by optical tweezers single molecule/single cell and other biophysical measurements...
August 2018: Trends in Immunology
https://www.readbyqxmd.com/read/30053426/isolation-of-a-structural-mechanism-for-uncoupling-t-cell-receptor-signaling-from-peptide-mhc-binding
#7
Leah V Sibener, Ricardo A Fernandes, Elizabeth M Kolawole, Catherine B Carbone, Fan Liu, Darren McAffee, Michael E Birnbaum, Xinbo Yang, Laura F Su, Wong Yu, Shen Dong, Marvin H Gee, Kevin M Jude, Mark M Davis, Jay T Groves, William A Goddard, James R Heath, Brian D Evavold, Ronald D Vale, K Christopher Garcia
TCR-signaling strength generally correlates with peptide-MHC binding affinity; however, exceptions exist. We find high-affinity, yet non-stimulatory, interactions occur with high frequency in the human T cell repertoire. Here, we studied human TCRs that are refractory to activation by pMHC ligands despite robust binding. Analysis of 3D affinity, 2D dwell time, and crystal structures of stimulatory versus non-stimulatory TCR-pMHC interactions failed to account for their different signaling outcomes. Using yeast pMHC display, we identified peptide agonists of a formerly non-responsive TCR...
July 26, 2018: Cell
https://www.readbyqxmd.com/read/30042420/interferon-gene-therapy-reprograms-the-leukemia-microenvironment-inducing-protective-immunity-to-multiple-tumor-antigens
#8
Giulia Escobar, Luigi Barbarossa, Giulia Barbiera, Margherita Norelli, Marco Genua, Anna Ranghetti, Tiziana Plati, Barbara Camisa, Chiara Brombin, Davide Cittaro, Andrea Annoni, Attilio Bondanza, Renato Ostuni, Bernhard Gentner, Luigi Naldini
Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses...
July 24, 2018: Nature Communications
https://www.readbyqxmd.com/read/30039400/in-silico-drug-design-non-peptide-mimetics-for-the-immunotherapy-of-multiple-sclerosis
#9
Haralambos Tzoupis, Theodore Tselios
Advances in theoretical chemistry have led to the development of various robust computational techniques employed in drug design. Pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulations have been extensively applied, separately or in combination, in the design of potent molecules. The techniques involve the identification of a potential drug target (e.g., protein) and its subsequent characterization. The next step in the process comprises the development of a map describing the interaction patterns between the target molecule and its natural substrate...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/30038626/anti-cd3-fab-fragments-enhance-tumor-killing-by-human-%C3%AE-%C3%AE-t-cells-independent-of-nck-recruitment-to-the-%C3%AE-%C3%AE-t-cell-antigen-receptor
#10
Claudia Juraske, Piyamaporn Wipa, Anna Morath, Jose Villacorta Hidalgo, Frederike A Hartl, Katrin Raute, Hans-Heinrich Oberg, Daniela Wesch, Paul Fisch, Susana Minguet, Sutatip Pongcharoen, Wolfgang W Schamel
T lymphocytes expressing the γδ T cell receptor (γδ TCR) can recognize antigens expressed by tumor cells and subsequently kill these cells. γδ T cells are indeed used in cancer immunotherapy clinical trials. The anti-CD3ε antibody UCHT1 enhanced the in vitro tumor killing activity of human γδ T cells by an unknown molecular mechanism. Here, we demonstrate that Fab fragments of UCHT1, which only bind monovalently to the γδ TCR, also enhanced tumor killing by expanded human Vγ9Vδ2 γδ T cells or pan-γδ T cells of the peripheral blood...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/30027584/clonal-distribution-and-intratumor-heterogeneity-of-b-cell-repertoire-in-esophageal-squamous-cell-carcinoma
#11
Chaoting Zhang, Hongying Huang, Yu Miao, Hongchao Xiong, Zheming Lu
Recent successes in tumour immunotherapies have highlighted importance of tumour immunity. However, most previous studies to date have focused on T cell immune response, although B cells are key players in the core immune network and are associated with T-cell immune response. Based on our previous study delineating T cell receptor (TCR) repertoire in seven patients with esophageal squamous cell carcinoma (ESCC), this study profiled BCR repertoire of multiple tumour regions, adjacent normal tissue and blood from the same seven patients to reveal characteristics of B cell immunity and relationship to TCR repertoire in ESCC patients...
July 20, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/30027154/diacylglycerol-kinase-%C3%AE-dgk%C3%AE-and-casitas-b-lineage-proto-oncogene-b-deficient-mice-have-similar-functional-outcomes-in-t-cells-but-dgk%C3%AE-deficient-mice-have-increased-t-cell-activation-and-tumor-clearance
#12
Erin M Wesley, Gang Xin, Donna McAllister, Subramaniam Malarkannan, Debra K Newman, Michael B Dwinell, Weiguo Cui, Bryon D Johnson, Matthew J Riese
Targeting negative regulators downstream of the T cell receptor (TCR) represents a novel strategy to improve cancer immunotherapy. Two proteins that serve as critical inhibitory regulators downstream of the TCR are diacylglycerol kinase ζ (DGKζ), a regulator of Ras and PKC-θ signaling, and Casitas b-lineage proto-oncogene b (Cbl-b), an E3 ubiquitin ligase that predominantly regulates PI(3)K signaling. We sought to compare the signaling and functional effects that result from deletion of DGKζ, Cbl-b, or both (double knockout, DKO) in T cells, and to evaluate tumor responses generated in a clinically relevant orthotopic pancreatic tumor model...
April 1, 2018: ImmunoHorizons
https://www.readbyqxmd.com/read/30026870/distinct-immune-signatures-in-directly-treated-and-distant-tumors-result-from-tlr-adjuvants-and-focal-ablation
#13
Michael Chavez, Matthew T Silvestrini, Elizabeth S Ingham, Brett Z Fite, Lisa M Mahakian, Sarah M Tam, Asaf Ilovitsh, Arta M Monjazeb, William J Murphy, Neil E Hubbard, Ryan R Davis, Clifford G Tepper, Alexander D Borowsky, Katherine W Ferrara
Both adjuvants and focal ablation can alter the local innate immune system and trigger a highly effective systemic response. Our goal is to determine the impact of these treatments on directly treated and distant disease and the mechanisms for the enhanced response obtained by combinatorial treatments. Methods: We combined RNA-sequencing, flow cytometry and TCR-sequencing to dissect the impact of immunotherapy and of immunotherapy combined with ablation on local and systemic immune components. Results: With administration of a toll-like receptor agonist agonist (CpG) alone or CpG combined with same-site ablation, we found dramatic differences between the local and distant tumor environments, where the directly treated tumors were skewed to high expression of F4/80 , Cd11b and Tnf and the distant tumors to enhanced Cd11c , Cd3 and Ifng ...
2018: Theranostics
https://www.readbyqxmd.com/read/30021156/the-ubiquitin-ligase-adaptor-ndfip1-selectively-enforces-a-cd8-t-cell-tolerance-checkpoint-to-high-dose-antigen
#14
Mayura V Wagle, Julia M Marchingo, Jason Howitt, Seong-Seng Tan, Christopher C Goodnow, Ian A Parish
Escape from peripheral tolerance checkpoints that control cytotoxic CD8+ T cells is important for cancer immunotherapy and autoimmunity, but pathways enforcing these checkpoints are mostly uncharted. We reveal that the HECT-type ubiquitin ligase activator, NDFIP1, enforces a cell-intrinsic CD8+ T cell checkpoint that desensitizes TCR signaling during in vivo exposure to high antigen levels. Ndfip1-deficient OT-I CD8+ T cells responding to high exogenous tolerogenic antigen doses that normally induce anergy aberrantly expanded and differentiated into effector cells that could precipitate autoimmune diabetes in RIP-OVAhi mice...
July 17, 2018: Cell Reports
https://www.readbyqxmd.com/read/30011396/regulation-of-memory-cd8-t-cell-differentiation-by-micrornas
#15
Zhen Zhang, Chaoqi Zhang, Feng Li, Bin Zhang, Yi Zhang
MicroRNAs (miRNAs) have emerged as crucial regulators of T lymphocyte survival, differentiation and function, all of which are key factors impacting the outcome of adoptive T cell-based immunotherapy. It has become increasingly clear that the adoptive transfer of memory CD8+ T cell subsets is highly correlated with objective clinical responses for patients with advanced cancer. However, it is unclear how to improve the long-term persistence of transferred CD8+ T cells using miRNAs. Here, we highlight the current advances in our understanding of the role of miRNAs in regulating the differentiation of memory CD8+ T cells...
2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/30008257/survivin-peptide-vaccination-elicits-immune-response-after-allogeneic-nonmyeloablative-transplantation-a-safe-strategy-to-enhance-the-graft-versus-tumor-effect
#16
Paola Circosta, Katia Vitaggio, Angela Rita Elia, Maja Todorovic, Dario Sangiolo, Fabrizio Carnevale-Schianca, Antonella Vallario, Massimo Geuna, Massimo Aglietta, Alessandro Cignetti
Allogeneic hematopoietic cell transplantation (allo-HCT) is an adoptive immunotherapy strategy whose effectiveness relies on graft-versus-tumor (GVT) effect. We explored the feasibility of enhancing GVT after allo-HCT by peptide vaccination. Two myeloma patients were transplanted with a fludarabine-total body irradiation conditioning regimen and vaccinated with an HLA-A*0201-restricted modified survivin nonapeptide, plus montanide as adjuvant. At time of first vaccination, one patient had just attained serological remission despite documented relapse after transplant, while the other patient was in stable disease...
July 2018: Immunotherapy
https://www.readbyqxmd.com/read/30006565/co-expression-of-cd39-and-cd103-identifies-tumor-reactive-cd8-t-cells-in-human-solid-tumors
#17
Thomas Duhen, Rebekka Duhen, Ryan Montler, Jake Moses, Tarsem Moudgil, Noel F de Miranda, Cheri P Goodall, Tiffany C Blair, Bernard A Fox, Jason E McDermott, Shu-Ching Chang, Gary Grunkemeier, Rom Leidner, Richard Bryan Bell, Andrew D Weinberg
Identifying tumor antigen-specific T cells from cancer patients has important implications for immunotherapy diagnostics and therapeutics. Here, we show that CD103+ CD39+ tumor-infiltrating CD8 T cells (CD8 TIL) are enriched for tumor-reactive cells both in primary and metastatic tumors. This CD8 TIL subset is found across six different malignancies and displays an exhausted tissue-resident memory phenotype. CD103+ CD39+ CD8 TILs have a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery...
July 13, 2018: Nature Communications
https://www.readbyqxmd.com/read/30001747/isolation-of-t-cell-receptors-targeting-recurrent-neoantigens-in-hematological-malignancies
#18
Vanessa M Tubb, Deborah S Schrikkema, Nathan P Croft, Anthony W Purcell, Carsten Linnemann, Manon R Freriks, Frederick Chen, Heather M Long, Steven P Lee, Gavin M Bendle
Mutation-derived neoantigens represent an important class of tumour-specific, tumour rejection antigens, and are attractive targets for TCR gene therapy of cancer. The majority of such mutations are patient-specific and targeting these requires a fully personalized approach. However, some mutations are found recurrently among cancer patients, and represent potential targets for neoantigen-specific TCR gene therapy that is more widely applicable. Therefore, we have investigated if some cancer mutations found recurrently in hematological malignancies encode immunogenic neoantigens presented by common European Caucasoid HLA class I alleles and can form targets for TCR gene therapy...
July 13, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29997626/dissecting-epstein-barr-virus-specific-t-cell-responses-after-allogeneic-ebv-specific-t-cell-transfer-for-central-nervous-system-posttransplant-lymphoproliferative-disease
#19
Rebecca E Schultze-Florey, Sabine Tischer, Leonie Kuhlmann, Patrick Hundsdoerfer, Arend Koch, Ioannis Anagnostopoulos, Sarina Ravens, Lilia Goudeva, Christian Schultze-Florey, Christian Koenecke, Rainer Blasczyk, Ulrike Koehl, Hans-Gert Heuft, Immo Prinz, Britta Eiz-Vesper, Britta Maecker-Kolhoff
Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) with central nervous system (CNS) involvement is a severe complication after solid organ transplantation. Standard treatment with reduction of immunosuppression and anti-CD20 antibody application often fails leading to poor outcome. Here, we report the case of an 11-year-old boy with multilocular EBV-positive CNS PTLD 10 years after liver transplantation. Complete remission was achieved by repeated intravenous and intrathecal anti-CD20 antibody rituximab administration combined with intrathecal chemotherapy (methotrexate, cytarabine, prednisone) over a time period of 3 months...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29997621/single-cell-approach-to-influenza-specific-cd8-t-cell-receptor-repertoires-across-different-age-groups-tissues-and-following-influenza-virus-infection
#20
Sneha Sant, Ludivine Grzelak, Zhongfang Wang, Angela Pizzolla, Marios Koutsakos, Jane Crowe, Thomas Loudovaris, Stuart I Mannering, Glen P Westall, Linda M Wakim, Jamie Rossjohn, Stephanie Gras, Michael Richards, Jianqing Xu, Paul G Thomas, Liyen Loh, Thi H O Nguyen, Katherine Kedzierska
CD8+ T cells recognizing antigenic peptides derived from conserved internal viral proteins confer broad protection against distinct influenza viruses. As memory CD8+ T cells change throughout the human lifetime and across tissue compartments, we investigated how T cell receptor (TCR) composition and diversity relate to memory CD8+ T cells across anatomical sites and immunological phases of human life. We used ex vivo peptide-HLA tetramer magnetic enrichment, single-cell multiplex RT-PCR for both the TCR-alpha (TCRα) and TCR-beta (TCRβ) chains, and new TCRdist and grouping of lymphocyte interactions by paratope hotspots (GLIPH) algorithms to compare TCRs directed against the most prominent human influenza epitope, HLA-A*02:01-M158-66 (A2+ M158 )...
2018: Frontiers in Immunology
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