GIFT4 fusokine converts leukemic B cells into immune helper cells.

• Type of Material: Article
• Authors: Jiusheng Deng, Emory University; Andrea Pennati, Emory University; Jonathon Cohen, Emory University; Yuanqiang Wu, Emory University; Spencer Ng, Emory University; Jian Hui Wu, McGill University; Christopher Flowers, Emory University; Jacques Galipeau, Emory University
• Language: English
• Date: 2016
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © Deng et al. 2016. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12967-016-0865-1
• Title of Journal or Parent Work: Journal of Translational Medicine
• ISSN: 1479-5876
• Volume: 14
• Issue: 1
• Start Page: 106
• End Page: 106
• Grant/Funding Information: This work was supported by NIH (5R01AI093881) and Georgia Cancer Coalition (JG); the Winship Robbins Scholar Award and the Developmental Fund of the Winship Cancer Center Support Grant (5P30CA138292-06) (JD).
• Keywords: Chronic lymphocytic leukemia; Immunotherapy; T cells; GIFT4 fusokine
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology

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.