GIFT4 fusokine converts leukemic B cells into immune helper cells.
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.
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365B Clifton Road, Atlanta, GA, 30322, USA. jdeng2@emory.edu.
Jiusheng
J
Deng
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365B Clifton Road, Atlanta, GA, 30322, USA.
Andrea
A
Pennati
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365B Clifton Road, Atlanta, GA, 30322, USA.
Jonathon B
JB
Cohen
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365B Clifton Road, Atlanta, GA, 30322, USA.
Yuanqiang
Y
Wu
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365B Clifton Road, Atlanta, GA, 30322, USA.
Spencer
S
Ng
Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, Canada.
Jian Hui
JH
Wu
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365B Clifton Road, Atlanta, GA, 30322, USA.
Christopher R
CR
Flowers
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365B Clifton Road, Atlanta, GA, 30322, USA. jgalipe@emory.edu.
Jacques
J
Galipeau
D000328:Adult; D000368:Aged; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D045142:Cross-Priming / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010641:Phenotype; D020543:Proteome / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D020543:Proteome; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D053612:Janus Kinases
Chronic lymphocytic leukemia; GIFT4 fusokine; Immunotherapy; T cells