Indoleamine 2,3-dioxygenase, a new prognostic marker in sentinel lymph nodes of melanoma patients.
BACKGROUND
Indoleamine 2,3-dioxygenase (IDO), an enzyme with immunosuppressive properties is considered as a factor that impairs the antitumour immune response in melanoma. In this study, we investigated the expression of IDO in sentinel nodes of melanoma patients to determine its prognostic relevance.


METHODS
One hundred and sixteen melanoma patients were enrolled in this study with a median follow-up time after diagnosis of 71 months. The expression of IDO and forkhead box P3 (Foxp3) in the sentinel lymph nodes was determined by immunohistochemistry and correlated with progression-free survival and overall survival. In 42 patients, regulatory T cells were investigated by flow cytometry.


RESULTS
Cox regression survival analysis showed a significant negative effect of IDO expression on progression-free survival (p = 0.015) and overall survival (p = 0.010). High IDO expression was correlated with a significant higher frequency of Foxp3-positive cells in uninvaded lymph nodes (p = 0.016). The presence of IDO expression in the sentinel nodes was not associated with an increased frequency of circulating regulatory T cells (Tregs) but was significantly correlated with an increased mean fluorescence intensity of Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) in Tregs (p = 0.019). After CD3CD28 stimulation, peripheral blood mononuclear cells of patients with high IDO expression showed a lower production of interferon-gamma (IFN-γ) (p = 0.025).


CONCLUSIONS
This study points to an independent predictive role of IDO on survival, especially in melanoma patients with uninvolved sentinel nodes. Investigating IDO expression in the sentinel nodes of melanoma patients may be a useful marker to pre-identify patients with a less favourable prognosis in stage I and II disease.
Department of Dermatology, Ghent University Hospital, Ghent, Belgium. Reinhart.Speeckaert@ugent.be
Reinhart
R
Speeckaert
Karim
K
Vermaelen
Nanja
N
van Geel
Philippe
P
Autier
Jo
J
Lambert
Marc
M
Haspeslagh
Mireille
M
van Gele
Kris
K
Thielemans
Bart
B
Neyns
Nathalie
N
Roche
Natacha
N
Verbeke
Philippe
P
Deron
Marijn
M
Speeckaert
Lieve
L
Brochez
D000328:Adult; D060908:CTLA-4 Antigen / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008198:Lymph Nodes / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000175:diagnosis* / Q000401:mortality; D008875:Middle Aged; D011379:Prognosis; D021701:Sentinel Lymph Node Biopsy; D012878:Skin Neoplasms / Q000175:diagnosis* / Q000401:mortality; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma