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Acute lymphoblastic leukemia

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

Leukemia volume 30, pages 800–811 (2016)Cite this article

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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.

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Acknowledgements

We are thank the patients and their families for their cooperation. We are grateful to Amos Gaikwad and Tatiana Goltsova for flow cytometry assistance; Drs Cliona M Rooney and Natalia Lapteva for providing critical experimental components. This research was partially performed in the Flow Cytometry and Cellular Imaging Facility at MD Anderson Cancer Center, which is supported, in part, by the National Institutes of Health through MD Anderson's Cancer Center Support Grant CA016672. This research was funded, in part, by the MD Anderson Chronic Lymphocytic Leukemia Moon Shot Program. We also appreciate the support of shared resources by Dan L Duncan Cancer Center support grant P30CA125123. LLS SCOR (to CMB, KRR), Children’s Leukemia Research Association (to CMB, KRR), St Baldrick Scholar Award (to KRR), MDACC Leukemia SPORE Grant CA 100632 and SINF (to KR), Lymphoma SPORE P50CA126752 (to RHR) and NIH Training Grant T32 HL092332 (to RHR).

Author contributions

RHR designed research, performed research, analyzed data and wrote the paper. HS designed research, performed research and analyzed data. TS performed research and analyzed data. GW performed research. SK performed research. BB performed research. CB performed research. VM performed research. ES analyzed data. CMB designed research, analyzed data and wrote the paper. KRR designed research, analyzed data and wrote the paper. KR designed research, analyzed data and wrote the paper.

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Author notes

  1. K R Rabin and K Rezvani: These authors contributed equally to this work.

Authors and Affiliations

  1. Texas Children’s Cancer and Hematology Centers/Baylor College of Medicine, Houston, TX, USA

    R H Rouce, V Murali & K R Rabin

  2. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children’s Hospital, Houston, TX, USA

    R H Rouce, G Weber, B Ballard, S Ku, M-F Wu, H Liu & C M Bollard

  3. Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA

    H Shaim, T Sekine, E J Shpall & K Rezvani

  4. Program for Cell Enhancement and Technologies for Immunotherapy, and Center for Cancer and Immunology Research, Children's National Health System, Washington, DC, USA

    C Barese & C M Bollard

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Correspondence to K R Rabin or K Rezvani.

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

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