title: Defective STAT1 activation associated with impaired IFN-γ production in NK and T lymphocytes from metastatic melanoma patients treated with IL-2.
abstract: 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.
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Immunology, Moffitt Cancer Center, Tampa, FL 22612, USA.
authors.forename: Geok Choo
authors.initials: GC
authors.lastname: Sim
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Immunology, Moffitt Cancer Center, Tampa, FL 22612, USA.
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Radvanyi
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor; D007371:Interferon-gamma
keywords: IFN-γ; NK cells; STAT1; high-dose IL-2; melanoma