GIFT4 fusokine converts leukemic B cells into immune helper cells

• Published in: Journal of translational medicine Vol. 14; no. 1; p. 106
• Main Authors: Deng, Jiusheng, Pennati, Andrea, Cohen, Jonathon B., Wu, Yuanqiang, Ng, Spencer, Wu, Jian Hui, Flowers, Christopher R., Galipeau, Jacques
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27.04.2016; BioMed Central
• Subjects: Adult; Aged; Animals; Antigen-Presenting Cells - drug effects; Antigen-Presenting Cells - metabolism; B cells; Care and treatment; Cell Proliferation - drug effects; Cross-Priming - drug effects; Cytokines; Cytotoxicity, Immunologic - drug effects; Diagnosis; Female; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Humans; Immunotherapy; Interleukin-4 - pharmacology; Janus Kinases - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphocytic leukemia; Male; Mice; Middle Aged; Phenotype; Proteome - secretion; Recombinant Fusion Proteins - pharmacology; Signal Transduction - drug effects; STAT5 Transcription Factor - metabolism; T cells; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology; Chronic lymphocytic leukemia; T cells; Immunotherapy; GIFT4 fusokine
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-016-0865-1

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. 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. 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. 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.