Malignant B cells skew the balance of regulatory T cells and T H17 cells in B-cell non-Hodgkin's lymphoma

Zhi Zhang Yang, Anne J. Novak, Steven C. Ziesmer, Thomas E. Witzig, Stephen M. Ansell

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113 Scopus citations

Abstract

Using biopsy specimens from patients with B-cell non-Hodgkin's lymphoma, we observed a significantly low frequency of TH17cells, 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-17express ion 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 (Treg) cells, we tested the role of IL-2 signaling in TH17 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 Treg 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 Treg and TH17 cells resulting in the establishment of a profoundly inhibitory tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)5522-5530
Number of pages9
JournalCancer research
Volume69
Issue number13
DOIs
StatePublished - Jul 1 2009

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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