Effects of cyclophosphamide and IL-2 on regulatory CD4+ T cell frequency and function in melanoma patients vaccinated with HLA-class I peptides: impact on the antigen-specific T cell response

The frequency and function of regulatory T cells (Tregs) were studied in stage II–III melanoma patients who were enrolled in a phase II randomized trial of vaccination with HLA-A*0201-modified tumor peptides versus observation. The vaccinated patients received low-dose cyclophosphamide (CTX) and low...

Full description

Saved in:
Bibliographic Details
Published in:Cancer Immunology, Immunotherapy Immunotherapy, 2013-05, Vol.62 (5), p.897-908
Main Authors: Camisaschi, Chiara, Filipazzi, Paola, Tazzari, Marcella, Casati, Chiara, Beretta, Valeria, Pilla, Lorenzo, Patuzzo, Roberto, Maurichi, Andrea, Cova, Agata, Maio, Michele, Chiarion-Sileni, Vanna, Tragni, Gabrina, Santinami, Mario, Vergani, Barbara, Villa, Antonello, Berti, Emilio, Umansky, Ludmila, Beckhove, Philipp, Umansky, Viktor, Parmiani, Giorgio, Rivoltini, Licia, Castelli, Chiara
Format: Article
Language:English
Subjects:
Adult
Aged
Antigens, Neoplasm - immunology
Antineoplastic Agents, Alkylating - therapeutic use
Cancer Research
CD4-Positive T-Lymphocytes - cytology
CD8-Positive T-Lymphocytes - cytology
Cell Line, Tumor
Cyclophosphamide - therapeutic use
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Histocompatibility Antigens Class I - immunology
Humans
Immunology
Immunosuppressive Agents - therapeutic use
Immunotherapy - methods
Interferon-gamma - metabolism
Interleukin-2 - therapeutic use
Leukocytes, Mononuclear - cytology
Male
Medicine
Medicine & Public Health
Melanoma - drug therapy
Melanoma - metabolism
Middle Aged
Oncology
Original
Original Article
Phenotype
Skin Neoplasms - drug therapy
Skin Neoplasms - metabolism
T-Lymphocytes - cytology
Time Factors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The frequency and function of regulatory T cells (Tregs) were studied in stage II–III melanoma patients who were enrolled in a phase II randomized trial of vaccination with HLA-A*0201-modified tumor peptides versus observation. The vaccinated patients received low-dose cyclophosphamide (CTX) and low-dose interleukin-2 (IL-2). Tregs were analyzed in the lymph nodes (LNs) of stage III patients who were undergoing complete lymph node dissection and in peripheral blood mononuclear cells (PBMCs) collected before vaccination and at different time points during the vaccination period. The LNs of the vaccinated patients, which were surgically removed after two rounds of vaccination and one dose of CTX, displayed a low frequency of Tregs and a less immunosuppressive environment compared with those of the untreated patients. The accurate time-course analysis of the PBMCs of patients enrolled in the vaccination arm indicated a limited and transient modulation in the frequencies of Tregs in PBMCs collected after low-dose CTX administration and a strong Treg boost in those PBMCs collected after low-dose IL-2 administration. However, a fraction of the IL-2-boosted Tregs was functionally modulated to a Th-1-like phenotype in the vaccinated patients. Moreover, low-dose IL-2 promoted the concomitant expansion of conventional activated CD4 + T cells. Despite the amplification of Tregs, IL-2 administration maintained or further increased the number of antigen-specific CD8 + T cells that were induced by vaccination as demonstrated by the ex vivo human leukocyte antigen-multimer staining and IFN-γ ELISpot assays. Our study suggests that the use of CTX as a Treg modulator should be revised in terms of the administration schedule and of patients who may benefit from this drug treatment. Despite the Treg expansion that was observed in this study, low-dose IL-2 is not detrimental to the functional activities of vaccine-primed CD8 + T cell effectors when used in the inflammatory environment of vaccination.
ISSN:0340-7004
1432-0851
DOI:10.1007/s00262-013-1397-7