TGF-β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma

Z. Z. Yang, D. M. Grote, B. Xiu, S. C. Ziesmer, T. L. Price-Troska, L. S. Hodge, D. M. Yates, A. J. Novak, S. M. Ansell

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51 Scopus citations

Abstract

Transforming growth factor beta (TGF-β) has an important role in mediating T-cell suppression in B-cell non-Hodgkin lymphoma (NHL). However, the underlying mechanism responsible for TGF-β-mediated inhibition of effector memory T (T m) cells is largely unknown. As reported here, we show that exhaustion is a major mechanism by which TGF-β inhibits T m cells, and TGF-β mediated exhaustion is associated with upregulation of CD70. We found that TGF-β upregulates CD70 expression on effector T m cells while it preferentially induces Foxp3 expression in naive T cells. CD70 induction by TGF-β is Smad3-dependent and involves IL-2/Stat5 signaling. CD70 + T cells account for TGF-β-induced exhaustion of effector T m cells. Both TGF-β-induced and preexisting intratumoral CD70 + effector T m cells from B-cell NHL have an exhausted phenotype and express higher levels of PD-1 and TIM-3 compared with CD70 - T cells. Signaling transduction, proliferation and cytokine production are profoundly decreased in these cells, and they are highly susceptible to apoptosis. Clinically, intratumoral CD70-expressing T cells are prevalent in follicular B-cell lymphoma (FL) biopsy specimens, and increased numbers of intratumoral CD70 + T cells correlate with an inferior patient outcome. These findings confirm TGF-β-mediated effector T m cell exhaustion as an important mechanism of immune suppression in B-cell NHL.

Original languageEnglish (US)
Pages (from-to)1872-1884
Number of pages13
JournalLeukemia
Volume28
Issue number9
DOIs
StatePublished - Jan 1 2014

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ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Yang, Z. Z., Grote, D. M., Xiu, B., Ziesmer, S. C., Price-Troska, T. L., Hodge, L. S., Yates, D. M., Novak, A. J., & Ansell, S. M. (2014). TGF-β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma. Leukemia, 28(9), 1872-1884. https://doi.org/10.1038/leu.2014.84