title: Regulatory T-cell response and tumor vaccine-induced cytotoxic T lymphocytes in human melanoma.
abstract: A role of CD4(+) cells in the regulation of immune responses has steadily gained renewed recognition. The understanding of these T-regulatory (T-reg) cells in the generation of antitumor cytolytic T lymphocyte (CTL) response is therefore important. It has been shown that immunization with specific peptides, DNA, or tumor lysate-based vaccines can induce CTL responses in vivo. We have immunized melanoma patients with major histocompatibility complex (MHC) class I restricted peptide- or melanoma tumor lysate-loaded antigen-presenting cell (APC)-based vaccines and have monitored the generation of CTL responses and T-reg cell responses, if any. Using tetramer staining and limiting dilution analyses as monitors of CTL responses, we found significant increases in the number of antigen-specific CTL in circulation after vaccination with the MART-1(27-35) peptide (AAGIGILTV)-pulsed autologous APC, the MAGE-1(161-169) peptide (EADPTGHSY)-pulsed APC, or with autologous tumor lysate-pulsed APC. The antigen-specific CTL reached the peak expansion by day 7 and then declined to the prevaccine levels by day 28. The decline in the CTL response was associated by a concomitant expansion of CD4(+) CD25(+)T cells. Analysis of postvaccine peripheral blood lymphocytes (PBL) from patients showed an increased amount of interleukin (IL)-10 secretion on in vitro stimulation with IL-2 after successive vaccination. Triple color flow cytometric analyses revealed cytoplasmic IL-10 in the CD4(+)CD25(+) T-cell fraction and the number of CD4(+)CD25(+) IL-10(+) T cells were found to increase significantly in postvaccine PBL. These observations have implications in tumor antigen and APC/dendritic cell (DC)-based cancer vaccine strategies.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Connecticut Health Center, Farmington, CT., USA. chakraborty@uchc.edu
authors.forename: Nitya G
authors.initials: NG
authors.lastname: Chakraborty
authors.forename: Subhasis
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Shikhar
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Arvind
authors.initials: A
authors.lastname: Chhabra
authors.forename: Bijay
authors.initials: B
authors.lastname: Mukherji
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D015234:HLA-A Antigens / Q000737:chemistry / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D016753:Interleukin-10 / Q000032:analysis / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology*; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010455:Peptides / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D007519:Isoantigens; C072011:MAGEA1 protein, human; C415186:MART-1 antigen (27-35), Leu(28)-beta-HIle(30)-; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D010455:Peptides; D016753:Interleukin-10