Induction of a CTL-Like Phenotype In B-CLL Cells Stimulated with Interleukin 21 and CpG Oligodeoxynucleotides

Abstract 3906

Interleukin 21 (IL-21) and CpG oligodeoxynucleotides (CpG ODN) are two novel and highly promising agents for the treatment of hematological diseases. Recently, we reported that IL-21 and CpG ODN induce granzyme B (GrB) and GrB-dependent apoptosis in malignant B cells from patients with B chronic lymphocytic leukemia (B-CLL), but not in healthy peripheral B cells. Here we further characterized the factors accountable for the different apoptotic response of B-CLL cells versus normal B cells. GrB induction in B-CLL cells after stimulation with IL-21 and CpG ODN was associated with upregulation of molecules, which are normally involved in the differentiation of cytotoxic T lymphocytes (CTL) including T-bet, perforin, monokine-induced by interferon-gamma (MIG) and IP-10, a finding not observed in normal healthy B cells. Furthermore, the induction of GrB in B-CLL cells by IL-21 and CpG ODN required signaling via a JAK/STAT-dependent pathway, as suggested by upregulation of phosphorylated STAT1/3. Finally, stimulation of B-CLL cells with IL-21 and CpG ODN upregulated molecules involved in cell adhesion (CD54), antigen presentation (MHC class I), co-stimulation (CD40, CD86) and GrB uptake (CD222, mannose-6-phosphate receptor), suggesting B-CLL cells activated with IL-21 and CpG ODN are able to contact other immune cells and may be able to reabsorb secreted GrB. In summary, B-CLL cells can express factors involved in cytotoxic differentiation of CTL as well as GrB in response to stimulation with IL-21 and CpG ODN. Our data provide novel insights into the aberrant signaling state of B-CLL cells and may pave the way for the development of novel immunotherapeutic treatment approaches for B-CLL.