Regulatory T cell frequency in patients with melanoma with different disease stage and course, and modulating effects of high-dose interferon-alpha 2b treatment.
BACKGROUND
High-dose interferon-alpha 2b (IFN-alpha 2b) is the only approved systemic therapy in the United States for the adjuvant treatment of melanoma. The study objective was to explore the immunomodulatory mechanism of action for IFN-alpha 2b by measuring serum regulatory T cell (Treg), serum transforming growth factor-beta (TGF-beta), interleukin (IL)-10, and autoantibody levels in patients with melanoma treated with the induction phase of the high-dose IFN-alpha 2b regimen.


METHODS
Patients with melanoma received IFN-alpha 2b administered intravenously (20 MU/m2 each day from day 1 to day 5 for 4 consecutive weeks). Serum Treg levels were measured as whole lymphocytes in CD4+ cells using flow cytometry while TGF-beta, IL-10, and autoantibody levels were measured using enzyme-linked immunosorbent assays.


RESULTS
Twenty-two patients with melanoma received IFN-alpha 2b treatment and were evaluated for Treg levels. Before treatment, Treg levels were significantly higher in patients with melanoma when compared with data from 20 healthy subjects (P = 0.001; Mann-Whitney test). Although a trend for reduction of Treg levels following IFN-α 2b treatment was observed (average decrease 0.29% per week), statistical significance was not achieved. Subgroup analyses indicated higher baseline Treg levels for stage III versus IV disease (P = 0.082), early recurrence versus no recurrence (P = 0.017), deceased versus surviving patients (P = 0.021), and preoperative neoadjuvant versus postoperative adjuvant treatment groups (not significant). No significant effects were observed on the levels of TGF-beta, IL-10, and autoantibodies in patients with melanoma treated with IFN-alpha 2b.


CONCLUSIONS
Patients with melanoma in this study showed increased basal levels of Treg that may be relevant to their disease and its progression. Treg levels shifted in patients with melanoma treated with IFN-alpha 2b, although no firm conclusions regarding the role of Tregs as a marker of treatment response or outcome can be made at present.
Ascierto
Paolo A
PA
Unit of Medical Oncology and Innovative Therapy and Melanoma Cooperative Group, National Tumor Institute, Naples, Italy. paolo.ascierto@gmail.com
Napolitano
Maria
M
Celentano
Egidio
E
Simeone
Ester
E
Gentilcore
Giusy
G
Daponte
Antonio
A
Capone
Mariaelena
M
Caracò
Corrado
C
Calemma
Rosa
R
Beneduce
Gerardo
G
Cerrone
Margherita
M
De Rosa
Vincenzo
V
Palmieri
Giuseppe
G
Castello
Giuseppe
G
Kirkwood
John M
JM
Marincola
Francesco M
FM
Mozzillo
Nicola
N
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001323:Autoantibodies / Q000097:blood; D015704:CD4 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000097:blood; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D009367:Neoplasm Staging; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000097:blood; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001323:Autoantibodies; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D053645:Interleukin-2 Receptor alpha Subunit; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10