Research Papers:

Defective STAT1 activation associated with impaired IFN-γ production in NK and T lymphocytes from metastatic melanoma patients treated with IL-2

Geok Choo Sim, Sheng Wu, Lei Jin, Patrick Hwu and Laszlo G. Radvanyi _

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Oncotarget. 2016; 7:36074-36091. https://doi.org/10.18632/oncotarget.8683

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Geok Choo Sim1,2,*, Sheng Wu1,*, Lei Jin1, Patrick Hwu1, Laszlo G. Radvanyi1,2

1Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

2Department of Immunology, Moffitt Cancer Center, Tampa, FL 22612, USA

*These authors have contributed equally to this work

Correspondence to:

Laszlo G. Radvanyi, email: [email protected]

Keywords: melanoma, high-dose IL-2, STAT1, IFN-γ, NK cells

Received: September 11, 2015     Accepted: March 11, 2016     Published: April 11, 2016


High dose (HD) IL-2 therapy has been used for almost two decades as an immunotherapy for metastatic melanoma. IL-2 promotes the proliferation and effector function of T and NK cells through the tyrosine phosphorylation and activation of signal transducer and activator of transcription factors (STAT), especially STAT5. However, whether any defects in STAT activation exist in T and NK lymphocytes from melanoma patients are under debate. Here, we measured the extent of HD IL-2-induced phosphorylation of STAT5 and STAT1 in lymphocyte subsets from metastatic melanoma patients and healthy controls at a single cell level using flow cytometry. We found no defects in IL-2-induced STAT5 phosphorylation and induction of proliferation in T and NK cell subsets in vitro. This was confirmed by measuring ex vivo STAT5 activation in whole blood collected from patients during their first bolus HD IL-2 infusion. IL-2 also induced STAT1 phosphorylation via IFN-γ receptors in T and NK cell subsets through the release of IFN-γ by CD56hi and CD56lo NK cells. Further analysis revealed that melanoma patients had a sub-optimal STAT1 activation response linked to lower IL-2-induced IFN-γ secretion in both CD56hi and CD56low NK cell subsets. STAT1 activation in response to IL-2 also showed an age-related decline in melanoma patients not linked to tumor burden indicating a premature loss of NK cell function. Taken together, these findings indicate that, although STAT5 activation is normal in metastatic melanoma patients in response to IL-2, indirect STAT1 activation is defective owing to deficiencies in the NK cell response to IL-2.

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