scholarly journals WT1 Tumor Antigen is Overexpressed in Kaposi Sarcoma and is Regulated by KSHV vFLIP

2021 ◽  
Author(s):  
Ayana Morales ◽  
Caitlyn Genovese ◽  
Matthew Bott ◽  
Julio Alvarez ◽  
Sung Soo Mun ◽  
...  
Keyword(s):  
T Cell ◽  
Therapeutic Approach ◽  
Poor Prognosis ◽  
Wilms Tumor ◽  
Kaposi Sarcoma ◽  
Host Protein ◽  
People Living With Hiv ◽  
Potential Biomarker ◽  
Wilms Tumor 1

AbstractPurposeWilms’ tumor 1 (WT1) is overexpressed in several cancers, and WT1 expression levels are associated with poor prognosis. As a host protein that functions as an oncogene, it represents an important immunotherapeutic target. This study evaluated WT1 expression in Kaposi sarcoma (KS) tumors to assess whether immunotherapy targeting WT1 is a potential therapeutic approach for KS. We also investigated the role of the causal agent of KS, Kaposi sarcoma herpesvirus (KSHV/HHV-8) in regulating WT1 expression.Experimental designImmunohistochemistry for WT1, KSHV, and B and T cells subsets, followed by image analysis, was performed in 363 KS tumor biopsies. Expression of KSHV vFLIP was evaluated by immunofluorescence. Primary endothelial cell cultures and cell lines were infected with KSHV in vitro, or transduced with an inducible vFLIP vector and induced with doxycycline, and then assessed for WT1 expression. Binding of ESK-1, a T cell receptor mimic therapeutic antibody that recognizes WT1 peptides presented on MHC HLA-A0201, was assessed using flow cytometry.ResultsWe report overexpression of WT1 in KS tumors, which was associated with increased with increasing histopathologic stage and the proportion of KSHV-infected cells. Areas with high WT1 expression showed sparse T cell infiltrates. KSHV infection in vitro resulted in WT1 upregulation, mediated by the viral protein vFLIP, which resulted in stronger binding of ESK1.ConclusionsKS lesions express high levels of WT1, a process regulated by the KSHV-encoded vFLIP. These findings suggest that immunotherapy directed against WT1 may represent a therapeutic approach for this cancer.Translational RelevanceKaposi sarcoma (KS) is a vascular neoplasm caused by the Kaposi sarcoma herpesvirus (KSHV/HHV-8). People living with HIV are not only at a significantly higher risk of developing KS, but also often have a more aggressive clinical course. Although antiretroviral therapy may cause regression of HIV-associated KS lesions, advanced cases of KS also require chemotherapy, which is rarely curative. Wilms’ tumor 1 (WT1) has been reported to be overexpressed in various cancers, functioning as an oncogene and associated with a poor prognosis. WT1 is also an important immunotherapeutic target, with several WT1-directed therapies showing promising results in early clinical trials for leukemias and solid tumors. Here we report high expression of WT1 in KS, especially in higher histological stages. Our findings provide pre-clinical evidence that supports conducting anti-WT1 immunotherapy trials in KS, and evaluating WT1 expression as a potential biomarker to identify individuals most likely to benefit.

Wilms´Tumor 1 Protein Is Highly Expressed on Malignant Plasma Cells and Provides a Novel Target for Immunotherapeutic Approaches

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 98-98 ◽  
Author(s):  
Guenther Koehne ◽  
Satyajit Kosuri ◽  
Ekaterina Doubrovina ◽  
Tao Dao ◽  
Andrew Scott ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Therapeutic Potential ◽  
Wilms Tumor ◽  
Human Igg1 ◽  
Wilms Tumor 1

Abstract Introduction: The Wilms' tumor 1 (WT1) protein is a tumor associated antigen that is potentially targetable by immunotherapeutic approaches. We have demonstrated the overexpression of WT1 in myeloma cells by IHC and in HLA-A*0201+ pts by staining with a high-affinity fully human IgG1 mAb (ESK1) specific to the RMFPNAPYL/HLA-A*0201 complex on malignant plasma cells. We report initial results from pts with plasma cell leukemia (PCL) or relapsed/refractory multiple myeloma (rMM) who have been treated with CD34-selected allo transplants followed by the administration of donor-derived WT1-specific T-cell infusions to induce an immunotherapeutic effect. Methods: In situ expression of WT1 was assessed by IHC analyses using a sequential double staining technique of MoAbs specific for CD138 and WT1.For staining with the RMFPNAPYL/HLA-A*0201 complex, BM samples were blocked with human FcR Blocking Reagent and then directly stained with MoAbs specific for CD38, CD56, CD45 and ESK1 or its isotype control human IgG1 and were analyzed by flow cytometry. WT1-specific T cells were generated from the original stem cell donors by sensitization of CD3+ enriched T-cell fractions with autologous APCs loaded with the pool of overlapping pentadecapeptides of WT1 (Invitrogen, Boston, MA). Cells were propagated in vitro with weekly restimulation and supplementation with IL-2 beginning at day 10-16. After 35-49 days, T-cells were harvested, counted and tested for antigen specific cytotoxicity, HLA-restriction, lack of alloreactivity and sterility. Pts received CD34-selected PBSC allografts after myeloablative cytoreduction with busulfan, melphalan and fludarabine. Pts were treated with 3 infusions of donor-derived WT1-specific T-cell infusions (5x10e6 cells/kg) starting 6 weeks post allo HSCT and at 4 weekly thereafter. Results: Marrow from all pts with immunohistochemical documented plasma cell involvement stained positive for WT1 IHC while WT1 staining remained negative in pts in CR. Only pts expressing HLA-A*0201 that stained positively for WT1 by IHC also demonstrated expression of WT1 by the RMFPNAPYL/HLA-A*0201 complex, whereas pts lacking HLA-A*0201 but with active disease stained positive for WT1 IHC but not ESK1 staining. Of 7 pts, 3 PCL and 4 rMM, treated with WT1-specific T cells, 4 pts had persistent disease post CD34-selected allotransplant. Of these 4 pts 2 pts developed a striking rise of WT1-specific T-cell frequencies and developed a complete remission post WT1 CTL infusions lasting for >2years. Conclusion: WT1 is overexpressed on malignant plasma cells and serves as a target for potential immunotherapeutic approaches in pts with multiple myeloma. Pts with persistent PCL following CD34-selected allografts treated with adoptive transfer of donor-derived WT1-specific cytotoxic T cells can achieve long lasting remission underscoring the therapeutic potential of T-cells specific for immunogenic WT1 peptides expressed on malignant plasma cells. Disclosures O'Reilly: Atara Biotherapeutics: Research Funding.

scholarly journals PD-1 dependent expansion of Amphregulin+FOXP3+ cells is associated with oral immune dysfunction in HIV patients on therapy

2021 ◽  
Author(s):  
N Bhaskaran ◽  
E Schneider ◽  
F Faddoul ◽  
A Paes da Silva ◽  
R Asaad ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Oral Mucosa ◽  
Immune Dysfunction ◽  
People Living With Hiv ◽  
Dependent Manner ◽  
Mucosal Tissues ◽  
T Cell Regulation ◽  
Ifn Γ

AbstractResidual systemic inflammation and mucosal immune dysfunction persist in people living with HIV (PLWH) despite treatment with combined anti-retroviral therapy (cART), but the underlying immune mechanisms are poorly understood. Here we report an altered immune landscape involving upregulation of TLR- and inflammasome signaling, localized CD4+ T cell hyperactivation, and counterintuitively, an enrichment of CD4+CD25+FOXP3+ regulatory T cells (Tregs) in the oral mucosa of HIV+ patients on therapy. Using human oral tonsil cultures, we found that HIV infection causes an increase in a unique population of FOXP3+ cells expressing PD-1, IFN-γ, Amphiregulin (AREG), and IL-10. These cells persisted even in the presence of the anti-retroviral drug and underwent further expansion driven by TLR-2 ligands and IL-1β. IL-1β also promoted PD-1 upregulation in AKT1 dependent manner. PD-1 stabilized FOXP3 and AREG expression in these cells through a mechanism requiring the activation of Asparaginyl Endopeptidase (AEP). Importantly, these FOXP3+ cells were incapable of suppressing CD4+ T cells in vitro. Concurrently, HIV+ patients harbored higher levels of PD-1, IFN-γ, Amphiregulin (AREG), and IL-10 expressing FOXP3+ cells, which strongly correlated with CD4+ T cell hyperactivation, suggesting an absence of CD4+ T cell regulation in the oral mucosa. Taken together, this study provides insights into a novel mechanism of FOXP3+ cell dysregulation and reveals a critical link in the positive feedback loop of oral mucosal immune activation events in HIV+ patients on therapy.One Sentence SummaryHIV-induced immune dysfunction in lymphoid and mucosal tissues

scholarly journals Chemoimmunotherapy targeting Wilms’ tumor 1 (WT1)-specific cytotoxic T lymphocyte and helper T cell responses for patients with pancreatic cancer

2014 ◽  
Vol 3 (10) ◽  
pp. e958950 ◽  
Author(s):  
Shigeo Koido ◽  
Sadamu Homma ◽  
Masato Okamoto ◽  
Kazuki Takakura ◽  
Jianlin Gong ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Wilms Tumor ◽  
T Cell Responses ◽  
Helper T Cell ◽  
Cell Responses ◽  
Wilms Tumor 1

scholarly journals Identification of a Wilms’ tumor 1-derived immunogenic CD4+ T-cell epitope that is recognized in the context of common Caucasian HLA-DR haplotypes

Leukemia ◽  
2012 ◽  
Vol 27 (3) ◽  
pp. 748-750 ◽  
Author(s):  
S Anguille ◽  
F Fujiki ◽  
E L Smits ◽  
Y Oji ◽  
E Lion ◽  
...  
Keyword(s):  
T Cell ◽  
Wilms Tumor ◽  
Cell Epitope ◽  
Cd4 T Cell ◽  
T Cell Epitope ◽  
Hla Dr ◽  
Wilms Tumor 1

scholarly journals Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential

Leukemia ◽  
2015 ◽  
Vol 29 (11) ◽  
pp. 2238-2247 ◽  
Author(s):  
Q Zhao ◽  
M Ahmed ◽  
D V Tassev ◽  
A Hasan ◽  
T-Y Kuo ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Therapeutic Potential ◽  
Wilms Tumor ◽  
Cell Receptor ◽  
Affinity Maturation ◽  
Wilms Tumor 1

scholarly journals CircADARB1 serves as a new biomarker in natural killer T-cell lymphoma and a potential regulator of p-Stat3

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mei Mei ◽  
Yingjun Wang ◽  
Wenting Song ◽  
Zhaoming Li ◽  
Qilong Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Natural Killer T Cell ◽  
Potential Biomarker ◽  
Killer T Cell ◽  
Natural Killer T

Abstract Background Natural killer/T-cell lymphoma (NKTCL) is a rare and aggressive subtype of Non-Hodgkin’s Lymphoma. CircRNA has shown great potential to become a biomarker in plasma. In this study, we aimed to determine circRNA for its diagnostic and prognostic value and biological function in NKTCL. Method The circRNA microarray of plasma from NKTCL patients and healthy donors were conducted. The relative expressions of target circRNA were verified by qRT-PCR. We conducted function experiments in vitro and in vivo. Bioinformatics predicted the target miRNA of the target circRNA and the binding site was detected by the dual luciferase report assay. Downstream target protein was predicted and detected by western blot in vitro and immunohistochemistry in vivo. Result By analyzing the plasma circRNA microarrays in NKTCL, 6137 circRNAs were up-regulated and 6190 circRNAs were down-regulated. The relative expressions of circADARB1 were significantly higher in NKTCL patients. The knockdown of circADARB1 inhibited proliferation of NKTCL cells in vitro and in vivo. CircADARB1 could bind to miR-214-3p in the downstream and regulate the expression of p-Stat3. In nude mice tumor tissue, p-Stat3 was under-expressed in the circADARB1 knockdown group. Conclusion CircADARB1 was highly expressed in NKTCL plasma and circADARB1 was a potential biomarker to assist diagnosis and predict the response in NKTCL. CircADARB1 bound up to miR-214-3p and regulated p-Stat3.

scholarly journals The Splenic Microenvironment Is a Novel Site of Relapse Following ABT-199 Treatment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3800-3800
Author(s):  
Alessandra Di Grande ◽  
Sofie Piers ◽  
Pieter Van Vlierberghe ◽  
Triona Ni Chonghaile
Keyword(s):  
T Cell ◽  
Cell Line ◽  
Poor Prognosis ◽  
Hematologic Malignancy ◽  
Xenograft Model ◽  
Clinical Importance ◽  
Development Of Resistance ◽  
A Site

T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive hematologic malignancy arising from the transformation of immune T-cell lymphocytes. Early T-cell progenitor (ETP-ALL) is a subgroup particularly associated with a poor prognosis and a high risk for relapse. While the leukaemia initially develops in the thymus it spreads in the blood to the bone marrow, lymph nodes and often the spleen. Interestingly, splenomegaly was previously associated with a poor prognosis in leukemic patients. Recently, it was shown that ETP-ALL is dependent on the expression of the anti-apoptotic protein BCL-2, and is sensitive to inhibition with ABT-199, a BCL-2 specific BH3 mimetic. However, one issue with targeted agents, like ABT-199, is the development of resistance to treatment. Our aim was to determine potential in vivosites of resistance/relapse following ABT-199 treatment using a xenograft model of ETP-ALL. We confirmed that the ETP-ALL LOUCY cell line is BCL-2 dependent and then labelled it with luciferase to enable visualisation of the leukaemia in vivo. Following establishment of the leukaemia in NOD/SCID gamma mice, as assessed by hCD45+, the mice were randomised to receive vehicle control or 50 mg/kg ABT-199 by oral gavage daily for two weeks. While the mice were initially sensitive to ABT-199, the leukaemia started to progress while on treatment. Interestingly, there appeared to be a selective redistribution of the leukaemia to the spleen following ABT-199 treatment. Indeed, LOUCY cells isolated from the spleen of the mice had a reduced BCL-2 dependence, as assessed by BH3 profiling. The reduced BCL-2 dependence correlated with reduced BCL-2 expression at both the mRNA and protein level. Next, we confirmed that human splenic fibroblasts (HSF) co-cultured with the LOUCY cell line in vitro also altered BCL-2 dependence and expression using BH3 profiling and Western blotting. To identify potential splenic cytokines involved in the regulation of BCL-2 protein expression in ETP-ALL we performed a screening cytokine array. Upon co-culture of the LOUCY cells with HSF there was an increased expression of IL-6, this was confirmed using ELISA. Using an IL-6 receptor antibody we confirmed that blocking IL-6 receptor reversed the change in BCL-2 dependence in the presence of the splenic microenvironment. Lastly, we confirmed in a T-ALL patient-derived xenograft, that is BCL-2 dependent, that the splenic microenvironment alters the mitochondrial apoptotic threshold. Currently, there are reports in the literature of ETP-ALL patients being treated with ABT-199. While there have been numerous studies lately describing cell autonomous events leading to ABT-199 resistance, our novel finding that the splenic microenvironment is a site of relapse is potentially of great clinical importance for BCL-2 dependent leukemia's. Disclosures Ni Chonghaile: AbbVie: Research Funding.

scholarly journals High Wilms’ tumor 1 mRNA expression correlates with basal-like and ERBB2 molecular subtypes and poor prognosis of breast cancer

2012 ◽  
Vol 28 (4) ◽  
pp. 1231-1236 ◽  
Author(s):  
XIAO-WEI QI ◽  
FAN ZHANG ◽  
XIN-HUA YANG ◽  
LIN-JUN FAN ◽  
YI ZHANG ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Poor Prognosis ◽  
Molecular Subtypes ◽  
Wilms Tumor ◽  
Wilms Tumor 1
Sign in / Sign up

Export Citation Format

Share Document