scholarly journals Interleukin-2 inducible T-cell kinase: a potential prognostic biomarker and tumor microenvironment remodeling indicator for hepatocellular carcinoma

Aging ◽  
2021 ◽  
Author(s):  
Binhua Pan ◽  
Modan Yang ◽  
Xuyong Wei ◽  
Wangyao Li ◽  
Kun Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Prognostic Biomarker ◽  
Interleukin 2 ◽  
Inducible T Cell Kinase ◽  
Kinase A

scholarly journals Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT

2020 ◽  
Vol 11 ◽  
Author(s):  
Mahinbanu Mammadli ◽  
Weishan Huang ◽  
Rebecca Harris ◽  
Aisha Sultana ◽  
Ying Cheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Treatment Strategies ◽  
Receptor Expression ◽  
Hematopoietic Stem ◽  
Target Organs ◽  
Donor T Cells ◽  
Inducible T Cell Kinase

Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8+ and CD4+ donor T cells from Itk-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

scholarly journals A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment

2018 ◽  
Vol 6 (1) ◽  
Author(s):  
Yu-Tzu Liu ◽  
Tai-Chung Tseng ◽  
Ruey-Shyang Soong ◽  
Chun-Yi Peng ◽  
Yu-Hsing Cheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Covalent Inhibitors of Interleukin-2 Inducible T Cell Kinase (Itk) with Nanomolar Potency in a Whole-Blood Assay

2012 ◽  
Vol 55 (22) ◽  
pp. 10047-10063 ◽  
Author(s):  
Christoph W. Zapf ◽  
Brian S. Gerstenberger ◽  
Li Xing ◽  
David C. Limburg ◽  
David R. Anderson ◽  
...  
Keyword(s):  
T Cell ◽  
Whole Blood ◽  
Interleukin 2 ◽  
Whole Blood Assay ◽  
Blood Assay ◽  
Covalent Inhibitors ◽  
Inducible T Cell Kinase

A PHASE 1/1B DOSE-ESCALATION TRIAL EVALUATING CPI-818, AN ORAL INTERLEUKIN-2-INDUCIBLE T-CELL KINASE INHIBITOR, IN PATIENTS WITH RELAPSED/REFRACTORY T-CELL LYMPHOMA

2019 ◽  
Vol 37 ◽  
pp. 563-564
Author(s):  
M. Mobasher ◽  
R. Miller ◽  
J. Janc ◽  
L. Kwei ◽  
C. Barker ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Interleukin 2 ◽  
T Cell Lymphoma ◽  
Inducible T Cell Kinase

scholarly journals Magnesium Restores Activity to Peripheral Blood Cells in a Patient With Functionally Impaired Interleukin-2-Inducible T Cell Kinase

2019 ◽  
Vol 10 ◽  
Author(s):  
Matthew K. Howe ◽  
Kennichi Dowdell ◽  
Amitava Roy ◽  
Julie E. Niemela ◽  
Wyndham Wilson ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Interleukin 2 ◽  
Peripheral Blood Cells ◽  
Functionally Impaired ◽  
Inducible T Cell Kinase

scholarly journals Interleukin-2–inducible T-cell kinase inhibitors modify functional polarization of human peripheral T-cell lymphoma cells

2019 ◽  
Vol 3 (5) ◽  
pp. 705-710
Author(s):  
Sami Mamand ◽  
Matthew Carr ◽  
Rebecca L. Allchin ◽  
Matthew J. Ahearne ◽  
Simon D. Wagner
Keyword(s):  
T Cell ◽  
Kinase Inhibitors ◽  
Interleukin 2 ◽  
Culture Conditions ◽  
Human Tonsil ◽  
Functional Changes ◽  
Key Points ◽  
Normal Human ◽  
Functional Polarization ◽  
Inducible T Cell Kinase

Key Points ITK inhibitors perturb functional changes due to polarizing culture conditions in normal human tonsil CD4+ T cells. Primary human PTCL cells alter their functional properties in culture and ITK inhibitors modify these changes.

scholarly journals Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity

2020 ◽  
Vol 8 (1) ◽  
pp. e000188 ◽  
Author(s):  
João Manuel Santos ◽  
Camilla Heiniö ◽  
Victor Cervera-Carrascon ◽  
Dafne C A Quixabeira ◽  
Mikko Siurala ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Ovarian Tumor ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Oncolytic Adenovirus ◽  
Adoptive T Cell Therapy ◽  
Necrosis Factor Alpha ◽  
T Cell Therapy ◽  
Potent Tumor

BackgroundOvarian cancers often contain significant numbers of tumor-infiltrating lymphocytes (TILs) that can be readily harnessed for adoptive T-cell therapy (ACT). However, the immunosuppressive ovarian tumor microenvironment and lack of tumor reactivity in TILs can limit the effectiveness of the therapy. We hypothesized that by using an oncolytic adenovirus (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) to deliver tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2), we could counteract immunosuppression, and enhance antitumor TIL responses in ovarian cancer (OVCA).MethodsWe established ex vivo tumor cultures freshly derived from patients with advanced OVCA and evaluated the effects of Ad5/3-E2F-D24-hTNFa-IRES-hIL2 or Ad5/3-E2F-D24 (the control virus without TNFa and IL-2) on TILs, cytokine response and tumor viability. Tumor reactivity was assessed by determining interferon gamma (IFNg) response of clinically relevant TILs towards autologous T-cell-depleted ex vivo tumor cultures pretreated with or without the aforementioned oncolytic adenoviruses.ResultsTreatment of ex vivo tumor cultures with Ad5/3-E2F-D24-hTNFa-IRES-hIL2 caused a substantial rise in proinflammatory signals: increased secretion of IFNg, CXCL10, TNFa and IL-2, and concomitant activation of CD4+ and CD8+ TILs. Potent tumor reactivity was seen, as clinically relevant TIL secreted high levels of IFNg in response to autologous T-cell-depleted ovarian ex vivo tumor cultures treated with Ad5/3-E2F-D24-hTNFa-IRES-hIL2. This phenomenon was independent of PD-L1 expression in tumor cells, a factor that determined the variability of IFNg responses seen in different patient samples.ConclusionsOverall, oncolytic adenovirus Ad5/3-E2F-D24-hTNFa-IRES-hIL2 was able to rewire the ovarian tumor microenvironment to accommodate heightened antitumor TIL reactivity. Such effects may improve the clinical effectiveness of ACT with TILs in patients with advanced OVCA.

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