Modulation of signal transducers and activators of transcription 1 and 3 signaling in melanoma by high-dose IFNalpha2b.
OBJECTIVE
The Janus-activated kinase/signal transducers and activators of transcription (STAT) pathway of IFN signaling is important to immunoregulation and tumor progression. STAT1 plays a prominent role in the effector immune response, whereas STAT3 is implicated in tumor progression and down-regulation of the response to type I IFNs. The goal of this study was to understand the effects of high-dose IFNalpha2b (HDI) in relation to the balance of pSTAT1 and pSTAT3.


METHODS
We evaluated STAT1 and STAT3 jointly as mediators of IFNalpha effects in the setting of a prospective neoadjuvant trial of HDI, in which tissue samples were obtained before and after 20 doses of HDI therapy. Double immunohistochemistry for pSTAT1 and pSTAT3 was done on paired fixed (9 patients) or frozen (12 patients) biopsies.


RESULTS
HDI was found to up-regulate pSTAT1, whereas it down-regulates pSTAT3 and total STAT3 levels in both tumor cells and lymphocytes. Higher pSTAT1/pSTAT3 ratios in tumor cells pretreatment were associated with longer overall survival (P = 0.032). The pSTAT1/pSTAT3 ratios were augmented by HDI both in melanoma cells (P = 0.005) and in lymphocytes (P = 0.022). Of the immunologic mediators and markers tested, TAP2 was augmented by HDI (but not TAP1 and MHC class I/II).


CONCLUSIONS
IFNalpha2b significantly modulates the balance of STAT1/STAT3 in tumor cells and host lymphocytes, leading to up-regulation of TAP2 and augmented host antitumor response. The pSTAT1/pSTAT3 ratio in tumor cells at baseline may serve as a useful predictor of clinical outcome in cutaneous melanoma; the modulation of this ratio may serve as a predictor of therapeutic effect.
Wang
Wenjun
W
Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh, Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute. Pittsburgh, PA, USA.
Edington
Howard D
HD
Rao
Uma N M
UN
Jukic
Drazen M
DM
Land
Stephanie R
SR
Ferrone
Soldano
S
Kirkwood
John M
JM
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000187:drug effects*; D050796:STAT3 Transcription Factor / Q000187:drug effects*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D014408:Biomarkers, Tumor; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C071692:TAP2 protein, human