title: Interferon signaling patterns in peripheral blood lymphocytes may predict clinical outcome after high-dose interferon therapy in melanoma patients.
abstract: BACKGROUND
  High-dose Interferon (HDI) therapy produces a clinical response and achieves relapse-free survival in 20-33% of patients with operable high risk or metastatic melanoma. However, patients may develop significant side effects frequently necessitating dose reduction or discontinuation of therapy. We recently showed that peripheral blood lymphocytes (PBL) from some melanoma patients have impaired interferon (IFN) signaling which could be restored with high concentrations of IFN. This exploratory study evaluated IFN signaling in PBL of melanoma patients to assess whether the restoration of PBL IFN signaling may predict a beneficial effect for HDI in melanoma patients.
  
  
  METHODS
  PBL from 14 melanoma patients harvested on Day 0 and Day 29 of neoadjuvant HDI induction therapy were analyzed using phosflow to assess their interferon signaling patterns through IFN-α induced phosphorylation of STAT1-Y701.
  
  
  RESULTS
  Patients who had a clinical response to HDI showed a lower PBL interferon signaling capacity than non-responders at baseline (Day 0). Additionally, clinical responders and patients with good long-term outcome showed a significant increase in their PBL interferon signaling from Day 0 to Day 29 compared to clinical non-responders and patients that developed metastatic disease. The differences in STAT1 activation from pre- to post- HDI treatment could distinguish between patients who were inclined to have a favorable or unfavorable outcome.
  
  
  CONCLUSIONS
  While the sample size is small, these results suggest that interferon signaling patterns in PBL correlate with clinical responses and may predict clinical outcome after HDI in patients with melanoma. A larger confirmatory study is warranted, which may yield a novel approach to select patients for HDI therapy.
authors.affiliation: Dept of Medicine, Stanford University, Stanford, CA, USA. KirkwoodJM@upmc.edu
authors.forename: Diana L
authors.initials: DL
authors.lastname: Simons
authors.forename: Gerald
authors.initials: G
authors.lastname: Lee
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Peter P
authors.initials: PP
authors.lastname: Lee
mesh_terms: D000368:Aged; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human