Functions of Anti-MAGE T-cells induced in melanoma patients under different vaccination modalities.
Tumor regressions have been observed in a small proportion of melanoma patients vaccinated with a MAGE-A3 peptide presented by HLA-A1, administered as peptide, ALVAC canarypox virus containing a MAGE-A3 minigene, or peptide-pulsed dendritic cells (DC). There was a correlation between tumor regression and the detection of anti-MAGE-3.A1 CTL responses. These responses were monoclonal and often of a very low magnitude after vaccination with peptide or ALVAC, and usually polyclonal and of a higher magnitude after DC vaccination. These results suggested that, at least in some patients, surprisingly few anti-MAGE-3.A1 T-cells could initiate a tumor regression process. To understand the role of these T cells, we carried out a functional analysis of anti-MAGE-3.A1 CTL clones derived from vaccinated patients who displayed tumor regression. The functional avidities of these CTL clones, evaluated in lysis assays, were surprisingly low, suggesting that high avidity was not part of the putative capability of these CTL to trigger tumor rejection. Most anti-MAGE-3.A1 CTL clones obtained after DC vaccination, but not after peptide or ALVAC vaccination, produced interleukin 10. Transcript profiling confirmed these results and indicated that approximately 20 genes, including CD40L, prostaglandin D2 synthase, granzyme K, and granzyme H, were highly differentially expressed between the anti-MAGE-3.A1 CTL clones derived from patients vaccinated with either peptide-ALVAC or peptide-pulsed DC. These results indicate that the modality of vaccination with a tumor-specific antigen influences the differentiation pathway of the antivaccine CD8 T-cells, which may have an effect on their capacity to trigger a tumor rejection response.
Connerotte
Thierry
T
de Duve Institute, Université Catholique de Louvain, Department of Physiology and Immunology, Medical School of Vrije Universiteit Brussel, Brussels, Belgium.
Van Pel
Aline
A
Godelaine
Danièle
D
Tartour
Eric
E
Schuler-Thurner
Beatrice
B
Lucas
Sophie
S
Thielemans
Kris
K
Schuler
Gerold
G
Coulie
Pierre G
PG
D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D023201:CD40 Ligand / Q000096:biosynthesis; D019496:Cancer Vaccines; D002450:Cell Communication; D003713:Dendritic Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015788:HLA-A1 Antigen / Q000737:chemistry*; D006801:Humans; D008545:Melanoma / Q000276:immunology* / Q000473:pathology*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000737:chemistry*; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000737:chemistry
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015788:HLA-A1 Antigen; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D010455:Peptides; D023201:CD40 Ligand