Multiplex analysis of serum cytokines in melanoma patients treated with interferon-alpha2b.
OBJECTIVE
Interferon (IFN)-alpha2b is the only Food and Drug Administration-approved treatment for operable high-risk melanoma that has been shown to significantly and durably prolong relapse-free survival (RFS) of patients with stage IIB-III melanoma. Development of reliable serum assays may contribute to the development of methods for earlier detection of melanoma and the selection of patients who may be most susceptible to current available interventions with IFNalpha.


METHODS
A powerful high-throughput xMAP multiplex immunobead assay technology (Luminex Corp., Austin, TX) was used to simultaneously test 29 cytokines, chemokines, angiogenic as well as growth factors, and soluble receptors in the sera of 179 patients with high-risk melanoma and 378 healthy individuals.


RESULTS
Serum concentrations of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-8, IL-12p40, IL-13, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, IFNalpha, tumor necrosis factor (TNF)-alpha, epidermal growth factor, vascular endothelial growth factor (VEGF), and TNF receptor II were found to be significantly higher in patients with resected high-risk melanoma compared with healthy controls. Bayesian Network algorithm classification of the data offered 90% sensitivity at 98% specificity with 96.5% of melanoma patients distinguished from healthy individuals. IFN-alpha2b therapy resulted in a significant decrease of serum levels of immunosuppressive and tumor angiogenic/growth stimulatory factors (VEGF, epidermal growth factor, and hepatocyte growth factor) and increased levels of antiangiogenic IFN-gamma inducible protein 10 (IP-10) and IFN-alpha. Pretreatment levels of proinflammatory cytokines IL-1beta, IL-1alpha, IL-6, TNF-alpha, and chemokines MIP-1alpha and MIP-1beta were found to be significantly higher in the serum of patients with longer RFS values of 1 to 5 and >5 years when compared with patients with shorter RFS of <1 year.


CONCLUSIONS
These data show that multiplexed analysis of serum biomarkers is useful for the evaluation of prognostic markers of clinical outcome and potential predictive markers of response to IFN-alpha2b in patients with high-risk operable melanoma.
Yurkovetsky
Zoya R
ZR
University of Pittsburgh Cancer Institute, Pennsylvania 15213, USA.
Kirkwood
John M
JM
Edington
Howard D
HD
Marrangoni
Adele M
AM
Velikokhatnaya
Lyudmila
L
Winans
Matthew T
MT
Gorelik
Elieser
E
Lokshin
Anna E
AE
D000970:Antineoplastic Agents / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007378:Interleukins / Q000097:blood; D008545:Melanoma / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D009367:Neoplasm Staging; D018579:Patient Selection; D011379:Prognosis; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery
D000970:Antineoplastic Agents; D016207:Cytokines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007378:Interleukins; D011994:Recombinant Proteins