The TGF-β/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia

R. H. Rouce, H. Shaim, T. Sekine, G. Weber, B. Ballard, S. Ku, C. Barese, V. Murali, M. F. Wu, Hao Liu, E. J. Shpall, C. M. Bollard, K. R. Rabin, K. Rezvani

Research output: Contribution to journalArticle

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Abstract

Natural killer (NK) cells are key components of the innate immune system, providing potent antitumor immunity. Here, we show that the tumor growth factor-β (TGF-β)/SMAD signaling pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia (ALL). We characterized NK cells in 50 consecutive children with B-ALL at diagnosis, end induction and during maintenance therapy compared with age-matched controls. ALL-NK cells at diagnosis had an inhibitory phenotype associated with impaired function, most notably interferon-γ production and cytotoxicity. By maintenance therapy, these phenotypic and functional abnormalities partially normalized; however, cytotoxicity against autologous blasts remained impaired. We identified ALL-derived TGF-β1 to be an important mediator of leukemia-induced NK cell dysfunction. The TGF-β/SMAD signaling pathway was constitutively activated in ALL-NK cells at diagnosis and end induction when compared with healthy controls and patients during maintenance therapy. Culture of ALL blasts with healthy NK cells induced NK dysfunction and an inhibitory phenotype, mediated by activation of the TGF-β/SMAD signaling pathway, and abrogated by blocking TGF-β. These data indicate that by regulating the TGF-β/SMAD pathway, ALL blasts induce changes in NK cells to evade innate immune surveillance, thus highlighting the importance of developing novel therapies to target this inhibitory pathway and restore antileukemic cytotoxicity.

Original languageEnglish (US)
Pages (from-to)800-811
Number of pages12
JournalLeukemia
Volume30
Issue number4
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

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Immune Evasion
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Natural Killer Cells
Intercellular Signaling Peptides and Proteins
Neoplasms
Phenotype
Cellular Structures
Therapeutics
Interferons
Immune System
Immunity
Leukemia

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Rouce, R. H., Shaim, H., Sekine, T., Weber, G., Ballard, B., Ku, S., ... Rezvani, K. (2016). The TGF-β/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia. Leukemia, 30(4), 800-811. https://doi.org/10.1038/leu.2015.327

The TGF-β/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia. / Rouce, R. H.; Shaim, H.; Sekine, T.; Weber, G.; Ballard, B.; Ku, S.; Barese, C.; Murali, V.; Wu, M. F.; Liu, Hao; Shpall, E. J.; Bollard, C. M.; Rabin, K. R.; Rezvani, K.

In: Leukemia, Vol. 30, No. 4, 01.04.2016, p. 800-811.

Research output: Contribution to journalArticle

Rouce, RH, Shaim, H, Sekine, T, Weber, G, Ballard, B, Ku, S, Barese, C, Murali, V, Wu, MF, Liu, H, Shpall, EJ, Bollard, CM, Rabin, KR & Rezvani, K 2016, 'The TGF-β/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia', Leukemia, vol. 30, no. 4, pp. 800-811. https://doi.org/10.1038/leu.2015.327
Rouce, R. H. ; Shaim, H. ; Sekine, T. ; Weber, G. ; Ballard, B. ; Ku, S. ; Barese, C. ; Murali, V. ; Wu, M. F. ; Liu, Hao ; Shpall, E. J. ; Bollard, C. M. ; Rabin, K. R. ; Rezvani, K. / The TGF-β/SMAD pathway is an important mechanism for NK cell immune evasion in childhood B-acute lymphoblastic leukemia. In: Leukemia. 2016 ; Vol. 30, No. 4. pp. 800-811.
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