1. GIFT4 fusokine converts leukemic B cells into immune helper cells.
- Author
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Jiusheng Deng, Pennati, Andrea, Cohen, Jonathon B., Yuanqiang Wu, Spencer Ng, Jian Hui Wu, Flowers, Christopher R., Galipeau, Jacques, Deng, Jiusheng, Wu, Yuanqiang, Ng, Spencer, and Wu, Jian Hui
- Subjects
CYTOKINES ,INTERLEUKINS ,CHRONIC lymphocytic leukemia ,B cells ,CYTOMETRY ,ANIMALS ,ANTIGEN presenting cells ,CARRIER proteins ,CELL physiology ,CELLULAR immunity ,CELLULAR signal transduction ,GRANULOCYTE-macrophage colony-stimulating factor ,IMMUNITY ,MICE ,RECOMBINANT proteins ,RESEARCH funding ,T cells ,PHENOTYPES ,PROTEOMICS ,JANUS kinases - Abstract
Background: Chronic lymphocytic leukemia (CLL) remains incurable with standard therapy, and is characterized by excessive expansion of monoclonal abnormal mature B cells and more regulatory immune properties of T cell compartment. Thus, developing novel strategies to enhance immune function merits further investigation as a possible therapy for CLL.Methods: We generated a fusion cytokine (fusokine) arising from the combination of human GM-CSF and IL-4 (named GIFT4). Primary CLL cells were treated with GIFT4 or GM-CSG and IL-4 in vitro. GIFT4-triggered STAT5 signaling in CLL cells was examined by Western blot. The phenotype and secretome of GIFT4-treated CLL cells (GIFT4-CLL cells), and the immune stimulatory function of GIFT4-CLL cells on autologous T cells were analyzed by flow cytometry and luminex assay.Results: GIFT4-CLL up-regulated the expression of co-stimulatory molecules CD40, CD80 and CD86 and adhesion molecule CD54. GIFT4-CLL cells secreted IL-1β, IL-6, ICAM-1 and substantial IL-2 relative to unstimulated CLL cells. GIFT4 treatment led to JAK1, JAK2 and JAK3-mediated hyper-phosphorylation of STAT5 in primary CLL cells, which is essential for GIFT4-triggered conversion of CLL cells. GIFT4-CLL cells directly propelled the expansion of autologous IFN-γ-producing CD314(+) cytotoxic T cells in vitro, and that these could lyse autologous CLL cells. Furthermore, administration of GIFT4 protein promoted the expansion of human T cells in NOD-scid IL2Rγ(null) immune deficient mice adoptively pre-transferred with peripheral blood mononuclear cells from subjects with CLL.Conclusion: GIFT4 has potent capability to converts primary CLL cells into APC-like immune helper cells that initiate a T cell driven anti-CLL immune response. [ABSTRACT FROM AUTHOR]- Published
- 2016
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