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Article ; Online: Tsyn-Seq: a T-cell Synapse-Based Antigen Identification Platform.

2024 Volume 12, Issue 5, Page(s) 530–543

Abstract: Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T ... the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible ... NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter ...

Abstract	Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library. See related Spotlight by Makani and Joglekar, p. 515.
MeSH term(s)	Humans ; Receptors, Antigen, T-Cell/immunology ; Receptors, Antigen, T-Cell/genetics ; T-Lymphocytes/immunology ; High-Throughput Nucleotide Sequencing ; Papillomavirus E7 Proteins/immunology ; Papillomavirus E7 Proteins/genetics ; Gene Library ; Antigen-Presenting Cells/immunology ; NFATC Transcription Factors/metabolism ; NFATC Transcription Factors/immunology ; Cell Line, Tumor ; NF-kappa B/metabolism ; Immunological Synapses/immunology ; Human papillomavirus 16/immunology ; Human papillomavirus 16/genetics ; Female
Chemical Substances	Receptors, Antigen, T-Cell ; Papillomavirus E7 Proteins ; NFATC Transcription Factors ; oncogene protein E7, Human papillomavirus type 16 ; NF-kappa B
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-23-0467
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Zs.A 7022: Show issues

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Article ; Online: Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of T

Nature immunology

2023 Volume 24, Issue 12, Page(s) 2108–2120

Abstract: Regulatory T cells (T ...

Abstract	Regulatory T cells (T
MeSH term(s)	Mice ; Animals ; T-Lymphocytes, Regulatory ; Interleukin-27 ; T-Lymphocytes, Helper-Inducer ; Immune Tolerance ; Immunity, Cellular ; Th17 Cells
Chemical Substances	Interleukin-27
Language	English
Publishing date	2023-11-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-023-01667-y
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: CD8 + T cell memory is sustained in mice by hepatic stellate cells.

Chen, Yi-Ting / Su, Yu-Chia / Or, Yee-Ern / Cheng, Chin-Fu / Kung, John T

Hepatology (Baltimore, Md.)

2023 Volume 77, Issue 5, Page(s) 1486–1498

Abstract: ... Homeostatic maintenance of memory CD8 + cytotoxic T cells (MemCD8TCs) is thought to be mediated by IL-15/IL ... lasting functional cytotoxic T cell memory. ...

Abstract	Background and aims: Long-lasting immunological memory is the ultimate goal of vaccination. Homeostatic maintenance of memory CD8 + cytotoxic T cells (MemCD8TCs) is thought to be mediated by IL-15/IL-15R heterodimer (15HD)-expressing myeloid cells. Nonmyeloid hepatic stellate cells (HSCs) also express 15HD, but their role in maintaining MemCD8TC homeostasis is unknown. Approach and results: We engineered a genetically engineered mouse in which IL-15R complementary DNA (cDNA) had been inserted in-frame with lecithin-retinol acyltransferase gene and bred onto an IL-15R-KO (15R-KO) genetic background (L15R) that expressed IL-15R in HSCs at normal levels, but not in other liver cells. Outside of the liver of L15R mice, IL-15R expression was found in a number of organs, but not in dendritic cells and macrophages. The low IL-15R expression in the bone marrow (BM) of L15R mice was eliminated by the reconstitution of lethally-irradiated L15R mice with 15R-KO BM to generate L15RC mice. Because MemCD8TC maintenance is mediated by 15HD, not empty IL-15R, 15HD content in L15R mice was determined and found for liver, lung, kidney, and heart. L15R and L15RC mice developed and maintained long-lasting, systemic antigen-specific MemCD8TCs that were efficacious against tumor growth and Listeria monocytogenes infection in an antigen-specific manner. Among the four organs with 15HD content, liver-associated MemCD8TCs were different from those found in the lung, kidney, and heart in two ways: (1) they were quantitatively the most numerous, and (2) they appeared uniquely in the form of clusters in a specialized structure, sinusoidal niches of the liver. Conclusions: The liver, the largest organ of the body, is endowed with the capability of effectuating long-lasting functional cytotoxic T cell memory.
MeSH term(s)	Mice ; Animals ; Hepatic Stellate Cells ; CD8-Positive T-Lymphocytes ; Receptors, Interleukin-15/metabolism ; Immunologic Memory ; Liver ; Mice, Inbred C57BL
Chemical Substances	Receptors, Interleukin-15
Language	English
Publishing date	2023-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.32788
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Zs.A 1660: Show issues

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Article ; Online: Excited State Vibrational Dynamics Reveals a Photocycle That Enhances the Photostability of the TagRFP-T Fluorescent Protein.

Yabushita, Atsushi / Cheng, Chia-Yun / Ko, Ying Kuan / Kobayashi, Takayoshi / Iwakura, Izumi / Jimenez, Ralph

The journal of physical chemistry. B

2024 Volume 128, Issue 5, Page(s) 1188–1193

Abstract: ... photostable variant TagRFP-T (TagRFP S158T) to characterize their initial photoreactions. We find significant ...

Abstract	High photostability is a desirable property of fluorescent proteins (FPs) for imaging, yet its molecular basis is poorly understood. We performed ultrafast spectroscopy on TagRFP and its 9-fold more photostable variant TagRFP-T (TagRFP S158T) to characterize their initial photoreactions. We find significant differences in their electronic and vibrational dynamics, including faster excited-state proton transfer and transient changes in the frequency of the
MeSH term(s)	Green Fluorescent Proteins/chemistry ; Protons
Chemical Substances	Green Fluorescent Proteins (147336-22-9) ; Protons
Language	English
Publishing date	2024-01-28
Publishing country	United States
Document type	Journal Article
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.3c07212
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Article ; Online: Identification of CD8 + T-Cell-Immune Cell Communications in Ileal Crohn's Disease.

Duong, Han G / Choi, Eunice J / Hsu, Paul / Chiang, Natalie R / Patel, Shefali A / Olvera, Jocelyn G / Liu, Yi Chia / Lin, Yun Hsuan / Yao, Priscilla / Wong, William H / Indralingam, Cynthia S / Tsai, Matthew S / Boland, Brigid S / Wang, Wei / Chang, John T

Clinical and translational gastroenterology

2023 Volume 14, Issue 5, Page(s) e00576

Abstract: ... a previously published computational approach, NicheNet, to predict immune cell types interacting with CD8 + T ... for CD8 + T-cell subsets in the pathogenesis of IBD, we focused our analyses on identifying ... the interactions of CD8 + T-cell subsets with other immune cells in the intestinal tissue microenvironment ...

Abstract	Introduction: Crohn's disease (CD) is a major subtype of inflammatory bowel disease (IBD), a spectrum of chronic intestinal disorders caused by dysregulated immune responses to gut microbiota. Although transcriptional and functional changes in a number of immune cell types have been implicated in the pathogenesis of IBD, the cellular interactions and signals that drive these changes have been less well-studied. Methods: We performed Cellular Indexing of Transcriptomes and Epitopes by sequencing on peripheral blood, colon, and ileal immune cells derived from healthy subjects and patients with CD. We applied a previously published computational approach, NicheNet, to predict immune cell types interacting with CD8 + T-cell subsets, revealing putative ligand-receptor pairs and key transcriptional changes downstream of these cell-cell communications. Results: As a number of recent studies have revealed a potential role for CD8 + T-cell subsets in the pathogenesis of IBD, we focused our analyses on identifying the interactions of CD8 + T-cell subsets with other immune cells in the intestinal tissue microenvironment. We identified ligands and signaling pathways that have implicated in IBD, such as interleukin-1β, supporting the validity of the approach, along with unexpected ligands, such as granzyme B, which may play previously unappreciated roles in IBD. Discussion: Overall, these findings suggest that future efforts focused on elucidating cell-cell communications among immune and nonimmune cell types may further our understanding of IBD pathogenesis.
MeSH term(s)	Humans ; Crohn Disease ; Ligands ; Inflammatory Bowel Diseases/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; Cell Communication
Chemical Substances	Ligands
Language	English
Publishing date	2023-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2581516-7
ISSN	2155-384X ; 2155-384X
ISSN (online)	2155-384X
ISSN	2155-384X
DOI	10.14309/ctg.0000000000000576
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Article ; Online: Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets.

Sun, Xiaoping / Nguyen, Thomas / Achour, Achouak / Ko, Annette / Cifello, Jeffrey / Ling, Chen / Sharma, Jay / Hiroi, Toyoko / Zhang, Yongqing / Chia, Chee W / Wood, William / Wu, Wells W / Zukley, Linda / Phue, Je-Nie / Becker, Kevin G / Shen, Rong-Fong / Ferrucci, Luigi / Weng, Nan-Ping

The Journal of clinical investigation

2022 Volume 132, Issue 17

Abstract: A diverse T cell receptor (TCR) repertoire is essential for protection against a variety ... repertoires, in both total and subsets of T cells, as well as their changes with age, are not fully ... T cell subsets using a unique molecular identifier-based (UMI-based) RNA-seq method. Thorough ...

Abstract	A diverse T cell receptor (TCR) repertoire is essential for protection against a variety of pathogens, and TCR repertoire size is believed to decline with age. However, the precise size of human TCR repertoires, in both total and subsets of T cells, as well as their changes with age, are not fully characterized. We conducted a longitudinal analysis of the human blood TCRα and TCRβ repertoire of CD4+ and CD8+ T cell subsets using a unique molecular identifier-based (UMI-based) RNA-seq method. Thorough analysis of 1.9 × 108 T cells yielded the lower estimate of TCR repertoire richness in an adult at 3.8 × 108. Alterations of the TCR repertoire with age were observed in all 4 subsets of T cells. The greatest reduction was observed in naive CD8+ T cells, while the greatest clonal expansion was in memory CD8+ T cells, and the highest increased retention of TCR sequences was in memory CD8+ T cells. Our results demonstrated that age-related TCR repertoire attrition is subset specific and more profound for CD8+ than CD4+ T cells, suggesting that aging has a more profound effect on cytotoxic as opposed to helper T cell functions. This may explain the increased susceptibility of older adults to novel infections.
MeSH term(s)	Adult ; Aged ; CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes ; Humans ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell, alpha-beta/genetics ; T-Lymphocyte Subsets
Chemical Substances	Receptors, Antigen, T-Cell ; Receptors, Antigen, T-Cell, alpha-beta
Language	English
Publishing date	2022-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI158122
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Article ; Online: The CXCL16-CXCR6 axis in glioblastoma modulates T-cell activity in a spatiotemporal context.

Frontiers in immunology

2024 Volume 14, Page(s) 1331287

Abstract: ... impacting these processes.: Methods: Our study investigates the role of the CXCR6/CXCL16 axis in T ... expression patterns affect T-cell engagement, focusing on the consequences for T-cell function ... within the tumor environment. Additionally, we assessed the significance of CXCR6 expression in T-cell activation ...

Abstract	Introduction: Glioblastoma multiforme (GBM) pathobiology is characterized by its significant induction of immunosuppression within the tumor microenvironment, predominantly mediated by immunosuppressive tumor-associated myeloid cells (TAMCs). Myeloid cells play a pivotal role in shaping the GBM microenvironment and influencing immune responses, with direct interactions with effector immune cells critically impacting these processes. Methods: Our study investigates the role of the CXCR6/CXCL16 axis in T-cell myeloid interactions within GBM tissues. We examined the surface expression of CXCL16, revealing its limitation to TAMCs, while microglia release CXCL16 as a cytokine. The study explores how these distinct expression patterns affect T-cell engagement, focusing on the consequences for T-cell function within the tumor environment. Additionally, we assessed the significance of CXCR6 expression in T-cell activation and the initial migration to tumor tissues. Results: Our data demonstrates that CXCL16 surface expression on TAMCs results in predominant T-cell engagement with these cells, leading to impaired T-cell function within the tumor environment. Conversely, our findings highlight the essential role of CXCR6 expression in facilitating T-cell activation and initial migration to tumor tissues. The CXCL16-CXCR6 axis exhibits dualistic characteristics, facilitating the early stages of the T-cell immune response and promoting T-cell infiltration into tumors. However, once inside the tumor, this axis contributes to immunosuppression. Discussion: The dual nature of the CXCL16-CXCR6 axis underscores its potential as a therapeutic target in GBM. However, our results emphasize the importance of carefully considering the timing and context of intervention. While targeting this axis holds promise in combating GBM, the complex interplay between TAMCs, microglia, and T cells suggests that intervention strategies need to be tailored to optimize the balance between promoting antitumor immunity and preventing immunosuppression within the dynamic tumor microenvironment.
MeSH term(s)	Humans ; Glioblastoma ; Receptors, CXCR6/metabolism ; T-Lymphocytes/metabolism ; Chemokine CXCL16/metabolism ; Microglia/metabolism ; Tumor Microenvironment
Chemical Substances	Receptors, CXCR6 ; Chemokine CXCL16 ; CXCR6 protein, human ; CXCL16 protein, human
Language	English
Publishing date	2024-01-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1331287
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Article ; Online: Association of TRAIL receptor with phosphatase SHP-1 enables repressing T cell receptor signaling and T cell activation through inactivating Lck.

Chyuan, I-Tsu / Liao, Hsiu-Jung / Tan, Tse-Hua / Chuang, Huai-Chia / Chu, Yu-Chuan / Pan, Meng-Hsun / Wu, Chien-Sheng / Chu, Ching-Liang / Sheu, Bor-Ching / Hsu, Ping-Ning

Journal of biomedical science

2024 Volume 31, Issue 1, Page(s) 33

Abstract: Background: T cell receptor (TCR) signaling and T cell activation are tightly regulated ... regulates T cell-mediated immune responses by directly inhibiting T cell activation without inducing ... apoptosis; however, the distinct signaling pathway that regulates T cell activation remains unclear ...

Abstract	Background: T cell receptor (TCR) signaling and T cell activation are tightly regulated by gatekeepers to maintain immune tolerance and avoid autoimmunity. The TRAIL receptor (TRAIL-R) is a TNF-family death receptor that transduces apoptotic signals to induce cell death. Recent studies have indicated that TRAIL-R regulates T cell-mediated immune responses by directly inhibiting T cell activation without inducing apoptosis; however, the distinct signaling pathway that regulates T cell activation remains unclear. In this study, we screened for intracellular TRAIL-R-binding proteins within T cells to explore the novel signaling pathway transduced by TRAIL-R that directly inhibits T cell activation. Methods: Whole-transcriptome RNA sequencing was used to identify gene expression signatures associated with TRAIL-R signaling during T cell activation. High-throughput screening with mass spectrometry was used to identify the novel TRAIL-R binding proteins within T cells. Co-immunoprecipitation, lipid raft isolation, and confocal microscopic analyses were conducted to verify the association between TRAIL-R and the identified binding proteins within T cells. Results: TRAIL engagement downregulated gene signatures in TCR signaling pathways and profoundly suppressed phosphorylation of TCR proximal tyrosine kinases without inducing cell death. The tyrosine phosphatase SHP-1 was identified as the major TRAIL-R binding protein within T cells, using high throughput mass spectrometry-based proteomics analysis. Furthermore, Lck was co-immunoprecipitated with the TRAIL-R/SHP-1 complex in the activated T cells. TRAIL engagement profoundly inhibited phosphorylation of Lck (Y394) and suppressed the recruitment of Lck into lipid rafts in the activated T cells, leading to the interruption of proximal TCR signaling and subsequent T cell activation. Conclusions: TRAIL-R associates with phosphatase SHP-1 and transduces a unique and distinct immune gatekeeper signal to repress TCR signaling and T cell activation via inactivating Lck. Thus, our results define TRAIL-R as a new class of immune checkpoint receptors for restraining T cell activation, and TRAIL-R/SHP-1 axis can serve as a potential therapeutic target for immune-mediated diseases.
MeSH term(s)	Humans ; Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Jurkat Cells ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism ; Signal Transduction ; Protein Tyrosine Phosphatases/genetics ; Protein Tyrosine Phosphatases/metabolism ; Phosphorylation ; Lymphocyte Activation ; Tyrosine/metabolism
Chemical Substances	Receptors, TNF-Related Apoptosis-Inducing Ligand ; Receptors, Antigen, T-Cell ; Protein Tyrosine Phosphatase, Non-Receptor Type 6 (EC 3.1.3.48) ; Protein Tyrosine Phosphatases (EC 3.1.3.48) ; Tyrosine (42HK56048U)
Language	English
Publishing date	2024-03-27
Publishing country	England
Document type	Journal Article
ZDB-ID	1193378-1
ISSN	1423-0127 ; 1021-7770
ISSN (online)	1423-0127
ISSN	1021-7770
DOI	10.1186/s12929-024-01023-8
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Zs.A 4037: Show issues

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Article ; Online: Anti-TIGIT antibody improves PD-L1 blockade through myeloid and T

Guan, Xiangnan / Hu, Ruozhen / Choi, Yoonha / Srivats, Shyam / Nabet, Barzin Y / Silva, John / McGinnis, Lisa / Hendricks, Robert / Nutsch, Katherine / Banta, Karl L / Duong, Ellen / Dunkle, Alexis / Chang, Patrick S / Han, Chia-Jung / Mittman, Stephanie / Molden, Nandini / Daggumati, Pallavi / Connolly, Wendy / Johnson, Melissa /

Abreu, Delvys Rodriguez / Cho, Byoung Chul / Italiano, Antoine / Gil-Bazo, Ignacio / Felip, Enriqueta / Mellman, Ira / Mariathasan, Sanjeev / Shames, David S / Meng, Raymond / Chiang, Eugene Y / Johnston, Robert J / Patil, Namrata S

Nature

2024 Volume 627, Issue 8004, Page(s) 646–655

Abstract: Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab ... ...

Abstract	Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone
MeSH term(s)	Animals ; Humans ; Mice ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/therapeutic use ; Antineoplastic Agents/therapeutic use ; B7-H1 Antigen/antagonists & inhibitors ; B7-H1 Antigen/immunology ; CD8-Positive T-Lymphocytes/immunology ; Dendritic Cells/immunology ; Drug Therapy, Combination ; Immune Checkpoint Inhibitors/immunology ; Immune Checkpoint Inhibitors/therapeutic use ; Macrophage Activation ; Myeloid Cells/immunology ; Neoplasms/drug therapy ; Neoplasms/immunology ; Receptors, IgG/immunology ; Receptors, Immunologic/immunology ; T-Lymphocytes, Regulatory/immunology ; Tumor Microenvironment/immunology ; Tumor-Associated Macrophages/immunology
Chemical Substances	Antibodies, Monoclonal ; Antineoplastic Agents ; atezolizumab (52CMI0WC3Y) ; B7-H1 Antigen ; Immune Checkpoint Inhibitors ; Receptors, IgG ; Receptors, Immunologic ; TIGIT protein, human ; T cell Ig and ITIM domain protein, mouse
Language	English
Publishing date	2024-02-28
Publishing country	England
Document type	Journal Article
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-024-07121-9
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 9: Show issues
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Article ; Online: Immunosuppressive Drug-Resistant Armored T-Cell Receptor T Cells for Immune Therapy of HCC in Liver Transplant Patients.

Hafezi, Morteza / Lin, Meiyin / Chia, Adeline / Chua, Alicia / Ho, Zi Zong / Fam, Royce / Tan, Damien / Aw, Joey / Pavesi, Andrea / Krishnamoorthy, Thinesh Lee / Chow, Wan Cheng / Chen, Wenjie / Zhang, Qi / Wai, Lu-En / Koh, Sarene / Tan, Anthony T / Bertoletti, Antonio

Hepatology (Baltimore, Md.)

2021 Volume 74, Issue 1, Page(s) 200–213

Abstract: Background and aims: HBV-specific T-cell receptor (HBV-TCR) engineered T cells have the potential ... immunosuppressive treatment required to prevent graft rejection. Our aim is to molecularly engineer TCR-T ... function of TCR-T cells in liver transplanted patients with HBV-HCC recurrence receiving HBV-TCR T ...

Abstract	Background and aims: HBV-specific T-cell receptor (HBV-TCR) engineered T cells have the potential for treating HCC relapses after liver transplantation, but their efficacy can be hampered by the concomitant immunosuppressive treatment required to prevent graft rejection. Our aim is to molecularly engineer TCR-T cells that could retain their polyfunctionality in such patients while minimizing the associated risk of organ rejection. Approach and results: We first analyzed how immunosuppressive drugs can interfere with the in vivo function of TCR-T cells in liver transplanted patients with HBV-HCC recurrence receiving HBV-TCR T cells and in vitro in the presence of clinically relevant concentrations of immunosuppressive tacrolimus (TAC) and mycophenolate mofetil (MMF). Immunosuppressive Drug Resistant Armored TCR-T cells of desired specificity (HBV or Epstein-Barr virus) were then engineered by concomitantly electroporating mRNA encoding specific TCRs and mutated variants of calcineurin B (CnB) and inosine-5'-monophosphate dehydrogenase (IMPDH), and their function was assessed through intracellular cytokine staining and cytotoxicity assays in the presence of TAC and MMF. Liver transplanted HBV-HCC patients receiving different immunosuppressant drugs exhibited varying levels of activated (CD39 Conclusions: We engineered TCR-T cells of desired specificities that transiently escape the immunosuppressive effects of TAC and MMF. This finding has important clinical applications for the treatment of HBV-HCC relapses and other pathologies occurring in organ transplanted patients.
MeSH term(s)	Carcinoma, Hepatocellular/pathology ; Carcinoma, Hepatocellular/surgery ; Carcinoma, Hepatocellular/virology ; Coculture Techniques ; Drug Resistance/genetics ; Graft Rejection/immunology ; Graft Rejection/pathology ; Graft Rejection/prevention & control ; Hep G2 Cells ; Hepatitis B/pathology ; Hepatitis B/surgery ; Hepatitis B/virology ; Hepatitis B virus/immunology ; Hepatitis B virus/metabolism ; Humans ; Immunotherapy, Adoptive/methods ; Liver/drug effects ; Liver/immunology ; Liver/pathology ; Liver/virology ; Liver Neoplasms/pathology ; Liver Neoplasms/surgery ; Liver Neoplasms/virology ; Liver Transplantation/adverse effects ; Mycophenolic Acid/pharmacology ; Mycophenolic Acid/therapeutic use ; Neoplasm Recurrence, Local/immunology ; Neoplasm Recurrence, Local/pathology ; Neoplasm Recurrence, Local/therapy ; Protein Engineering ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocytes/transplantation ; Tacrolimus/pharmacology ; Tacrolimus/therapeutic use
Chemical Substances	Receptors, Antigen, T-Cell ; Mycophenolic Acid (HU9DX48N0T) ; Tacrolimus (WM0HAQ4WNM)
Language	English
Publishing date	2021-06-02
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.31662
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In stock of ZB MED Cologne/Königswinter

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Kategorien

In stock of ZB MED Cologne/Königswinter

Order via subito