Malignant B Cells Skew the Balance of Regulatory T Cells and TH17 Cells in B-Cell Non-Hodgkin's Lymphoma

Abstract

Using biopsy specimens from patients with B-cell non-Hodgkin's lymphoma, we observed a significantly low frequency of T_H17 cells, including several samples with no detectable amount of interleukin (IL)-17–producing cells present in the tumor microenvironment. We found that, in the absence of lymphoma B cells, treatment with IL-1β/IL-6 or lipopolysaccharide (LPS) enhanced IL-17 expression in CD4⁺ T cells and this enhancement was attenuated when CD4⁺ T cells were cocultured with lymphoma B cells. Blockade of CD27-CD70 or CD28-CD80/86 interactions by anti-CD70 or anti-CD80/86 antibodies restored LPS-mediated induction of IL-17 expression in CD4⁺ T cells cocultured with lymphoma B cells. Because a subset of lymphoma B cells express IL-2 and given that IL-2 signaling is critically important in the development of regulatory T (T_reg) cells, we tested the role of IL-2 signaling in T_H17 cell development. We found that treatment with anti-IL-2 antibody to interrupt IL-2 signaling significantly inhibited Foxp3 expression in CD4⁺ T cells. In contrast, interruption of IL-2 signaling up-regulated IL-17 expression in CD4⁺ T cells and restored lymphoma-mediated down-regulation of IL-17–producing cells. Furthermore, the reversal of T_reg cell activity by LPS or CpG-A resulted in an enhancement of IL-17–producing cells. Taken together, our study indicated that lymphoma B cells play an important role in skewing the balance between T_reg and T_H17 cells resulting in the establishment of a profoundly inhibitory tumor microenvironment. [Cancer Res 2009;69(13):5522–30]