Abstract
BackgroundChronic 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.MethodsWe 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.ResultsGIFT4-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 IL2Rγnull immune deficient mice adoptively pre-transferred with peripheral blood mononuclear cells from subjects with CLL.ConclusionGIFT4 has potent capability to converts primary CLL cells into APC-like immune helper cells that initiate a T cell driven anti-CLL immune response.
Highlights
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
Human GIFT4 converts primary CLL B cells into antigen‐presenting cell phenotype We previously demonstrated that human GIFT4 could expand and reprogram normal human B cells into antitumor helper cells [11]
To check whether GIFT4 could promote the proliferation of CLL cells, the primary CLL B cells were labeled with CFSE dye, treated with human GIFT4 protein at a concentration of 2 ng/ml as previously described [11]
Summary
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. Developing novel strategies to enhance immune function merits further investigation as a possible therapy for CLL. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults, and it is characterized by excessive expansion of monoclonal abnormal mature B cells in peripheral blood, lymph node, spleen and bone marrow [1], and remains incurable with standard therapy [2, 3]. Developing novel strategies to enhance immune function merits further. Considering that CLL B cells express both IL-4R [14] and GM-CSFR [15], we tested whether GIFT4 could have stimulatory effect on CLL cells, and reprogram the leukemic B cells into immune helper cells. GIFT4converted CLL B cells (GIFT4-CLL cells) secreted IL-1β, IL-6, ICAM-1 and substantial IL-2, and primed autologous T cells from patients into IFN-γ-producing CD314+ CLL-killer cells
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