scholarly journals Patient-Derived Organoids Recapitulate Intrinsic Immune Landscapes and Progenitor Populations of Glioblastoma

2021 ◽  
Author(s):  
Fumihiro Watanabe ◽  
Ethan W. Hollingsworth ◽  
Jenna M. Bartley ◽  
Lauren Wisehart ◽  
Rahil Desai ◽  
...  
Keyword(s):  
T Cell Receptor ◽  
Immune Cells ◽  
Cell Receptor ◽  
Self Organization ◽  
Cell Populations ◽  
Tumor Evolution ◽  
Cellular Architecture ◽  
Metabolic States ◽  
Tumor Organoids

SummaryGlioblastoma stem cells (GSCs) are highly self-renewing, resistant to therapy, and are able to form lethal tumors1, 2. Tumor organoids have been developed to study tumor evolution1–4, and while GSCs can form organoids for glioblastoma multiforme, our understanding of their intrinsic immune, metabolic, genetic, and molecular programs is limited. To address this, we deeply characterized GSC-derived GBM organoids using a modified protocol (GBMOsm) from several patient-derived GSCs and found they develop into complex 3D tissues with unique self-organization, cancerous metabolic states, and burdensome genetic landscapes. We discovered that GBMOsc recapitulate the presence of two important cell populations thought to drive GBM progression, SATB2+ and HOPX+ progenitors. Despite being devoid of immune cells, transcriptomic analysis across GBMOsc revealed an immune-like molecular program, enriched in cytokine, antigen presentation and processing, T-cell receptor inhibitors, and interferon genes. We determined that SATB2+ and HOPX+ populations contribute to this immune and interferon landscape in GBM in vivo and GBMOsm. Our work deepens our understanding of the intrinsic molecular and cellular architecture of GSC-derived GBMO and defines a novel GBMOsc intrinsic immune-like program.

scholarly journals Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Koen Debackere ◽  
Lukas Marcelis ◽  
Sofie Demeyer ◽  
Marlies Vanden Bempt ◽  
Nicole Mentens ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
Cell Receptor ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Fusion Transcripts ◽  
Not Otherwise Specified

AbstractPeripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we perform RNA-sequencing of 18 cases and validate results in an independent cohort of 37 PTCL cases. We identify FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs.

Effects of exogenous interleukin-7 on human thymus function

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2851-2858 ◽  
Author(s):  
Yukari Okamoto ◽  
Daniel C. Douek ◽  
Richard D. McFarland ◽  
Richard A. Koup
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
De Novo ◽  
Quantitative Polymerase Chain Reaction ◽  
Cell Receptor ◽  
Cellular Division ◽  
Hematopoietic Stem ◽  
Human Thymus ◽  
Interleukin 7

Abstract Immune reconstitution is a critical component of recovery after treatment of human immunodeficiency virus (HIV) infection, cancer chemotherapy, and hematopoietic stem cell transplantation. The ability to enhance T-cell production would benefit such treatment. We examined the effects of exogenous interleukin-7 (IL-7) on apoptosis, proliferation, and the generation of T-cell receptor rearrangement excision circles (TRECs) in human thymus. Quantitative polymerase chain reaction demonstrated that the highest level of TRECs (14 692 copies/10 000 cells) was present in the CD1a+CD3−CD4+CD8+stage in native thymus, suggesting that TREC generation occurred following the cellular division in this subpopulation. In a thymic organ culture system, exogenous IL-7 increased the TREC frequency in fetal as well as infant thymus, indicating increased T-cell receptor (TCR) rearrangement. Although this increase could be due to the effect of IL-7 to increase thymocyte proliferation and decrease apoptosis of immature CD3− cells, the in vivo experiments using NOD/LtSz-scid mice given transplants of human fetal thymus and liver suggested that IL-7 can also directly enhance TREC generation. Our results provide compelling evidence that IL-7 has a direct effect on increasing TCR-αβ rearrangement and indicate the potential use of IL-7 for enhancing de novo naı̈ve T-cell generation in immunocompromised patients.

Dendritic cells, engineered to secrete a T-cell receptor mimic peptide, induce antigen-specific immunosuppression in vivo

2003 ◽  
Vol 21 (8) ◽  
pp. 903-908 ◽  
Author(s):  
Karsten Mahnke ◽  
Yingjie Qian ◽  
Jürgen Knop ◽  
Alexander H Enk
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Mimic Peptide ◽  
Specific Immunosuppression

scholarly journals In Vivo Selection of T-Cell Receptor Junctional Region Sequences by HLA-A2 Human T-Cell Lymphotropic Virus Type 1 Tax11-19 Peptide Complexes

2001 ◽  
Vol 75 (2) ◽  
pp. 1065-1071 ◽  
Author(s):  
Mineki Saito ◽  
Graham P. Taylor ◽  
Akiko Saito ◽  
Yoshitaka Furukawa ◽  
Koichiro Usuku ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Virus Type ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
Human T Cell ◽  
Cdr3 Region

ABSTRACT Using HLA-peptide tetrameric complexes, we isolated human T-cell lymphotrophic virus type 1 Tax peptide-specific CD8+ T cells ex vivo. Antigen-specific amino acid motifs were identified in the T-cell receptor Vβ CDR3 region of clonally expanded CD8+ T cells. This result directly confirms the importance of the CDR3 region in determining the antigen specificity in vivo.

scholarly journals High-throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in alopecia areata

JCI Insight ◽  
2018 ◽  
Vol 3 (19) ◽  
Author(s):  
Annemieke de Jong ◽  
Ali Jabbari ◽  
Zhenpeng Dai ◽  
Luzhou Xing ◽  
Dustin Lee ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
High Throughput ◽  
Alopecia Areata ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Cell Populations

scholarly journals 173 Expression of a membrane-tethered IL-15/IL-15 receptor fusion protein enhances the persistence of MSLN-targeted TRuC-T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A185-A185
Author(s):  
Michelle Fleury ◽  
Derrick McCarthy ◽  
Holly Horton ◽  
Courtney Anderson ◽  
Amy Watt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fusion Protein ◽  
T Cell Receptor ◽  
Cytokine Production ◽  
Cell Receptor ◽  
Great Promise ◽  
And Function

BackgroundAdoptive cell therapies have shown great promise in hematological malignancies but have yielded little progress in the context of solid tumors. We have developed T cell receptor fusion construct (TRuC®) T cells, which are equipped with an engineered T cell receptor that utilizes the full complement of TCR signaling subunits and recognizes tumor-associated antigens independent of HLA. In clinical trials, mesothelin (MSLN)-targeting TRuC-T cells (TC-210 or gavo-cel) have shown unprecedented results in patients suffering from advanced mesothelioma and ovarian cancer. To potentially increase the depth of response, we evaluated strategies that can promote intra-tumoral T cell persistence and function. Among the common ??-chain cytokines, IL-15 uniquely supports the differentiation and maintenance of memory T cell subsets by limiting terminal differentiation and conferring resistance to IL-2 mediated activation-induced cell death (AICD). In the studies described here, we evaluated the potential of IL-15 as an enhancement to TRuC-T cell phenotype, persistence and function against MSLN+ targets.MethodsPrimary human T cells were activated and transduced with a lentiviral vector encoding an anti-MSLN binder fused to CD3ε alone or co-expressed with a membrane-tethered IL-15rα/IL-15 fusion protein (IL-15fu). Transduced T cells were expanded for 9 days and characterized for expression of the TRuC, IL-15rα and memory phenotype before subjecting them to in vitro functional assays to evaluate cytotoxicity, cytokine production, and persistence. In vivo efficacy was evaluated in MHC class I/II deficient NSG mice bearing human mesothelioma xenografts.ResultsIn vitro, co-expression of the IL-15fu led to similar cytotoxicity and cytokine production as TC-210, but notably enhanced T-cell expansion and persistence upon repeated stimulation with MSLN+ cell lines. Furthermore, the IL-15fu-enhanced TRuC-T cells sustained a significantly higher TCF-1+ population and retained a stem-like phenotype following activation. Moreover, the IL-15fu-enhanced TRuCs demonstrated robust in vivo expansion and intra-tumoral accumulation as measured by ex vivo analysis of TRuC+ cells in the tumor and blood, with a preferential expansion of CD8+ T cells. Finally, IL-15fu-enhanced TRuC-T cells could be observed in the blood long after the tumors were cleared.ConclusionsThese pre-clinical studies suggest that the IL-15fu can synergize with TC-210 to increase the potency and durability of response in patients with MSLN+ tumors.Ethics ApprovalAll animal studies were approved by the respective Institutional Animal Care and Use Committees.

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