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

• Published in: Oncotarget 2016-06, Vol.7 (24), p.36074-36091
• Main Authors: Sim, Geok Choo, Wu, Sheng, Jin, Lei, Hwu, Patrick, Radvanyi, Laszlo G
• Format: Article
• Language: English
• Subjects: Adult; Aged; Female; Flow Cytometry; Humans; Interferon-gamma - biosynthesis; Interleukin-2 - therapeutic use; Killer Cells, Natural - metabolism; Male; Melanoma - drug therapy; Melanoma - metabolism; Melanoma - pathology; Middle Aged; Neoplasm Metastasis; Phosphorylation - drug effects; Research Paper; STAT1 Transcription Factor - metabolism; STAT5 Transcription Factor - metabolism; T-Lymphocytes - metabolism
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.8683

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.