Spécificité des lymphocytes T présents dans une tumeur humaine qui régresse après vaccination avec un antigène MAGE
(2006)
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- Authors
- Supervisors
- Coulie, Pierre
- Abstract
- Several small scale clinical trials of vaccination with MAGE antigens have been conducted in metastatic melanoma patients with measurable disease. Therapeutical benefits were observed only in a minority of patients, whatever the vaccine modality (peptides, proteins, recombinant viruses, dendritic cells). Vaccination with antigenic peptide MAGE-A3168-176 induced low level anti-vaccine CTL responses, which were correlated with tumor regressions. The very low frequencies of detectable anti-vaccine CTL in most of the regressor patients led us to examine the potential role of additional effectors of the tumor rejections. <BR> A detailed analysis was carried out with melanoma patient EB81, who showed tumor regression after vaccination with MAGE-A3168-176 and has remained disease-free for six years after vaccination. Anti-vaccine CTL are rare in the blood and in tumors, whereas anti-tumor CTL, directed against other tumor antigens than those of the vaccine, were found at 1,000 to 10,000 fold higher frequencies. These anti-tumor T cells were already present at high frequency before vaccination. Two groups of anti-tumor CTL clones are present in the metastases. Some anti-tumor CTL clones were already present before vaccination, indicating that a spontaneous anti-tumor CTL response occured and became inefficient at halting tumor progression. Other CTL clones appeared after vaccination and were found to be highly enriched in regressing metastases relative to the blood. <BR> This work completes the analysis of anti-tumor CTL by identifying the antigens recognized by CTL clone 101, which appeared after vaccination, and CTL clone 10, which was already present before vaccination. <BR> CTL 101 was isolated from T lymphocytes from a metastatic lymph node. The antigenic peptide, presented by HLA-A2 molecules, is encoded by a mutated sequence in the gene coding for ClpP, a mitochondrial protease. Lysis of the tumor cells by the CTL was strongly increased by IFN-? treatment, because of a better processing of the antigenic peptide by the immunoproteasome. This could have contributed to tumor regression because a higher expression level of IFN-? was found in the regressing metastases as compared to a metastasis resected before vaccination. CTL clone 101 is also the only anti-tumor CTL clone directed against an antigenic peptide that was apparently not targeted by the spontaneous anti-tumor T cell responses that occured before vaccination. <BR> CTL clone 10, which was present in the blood and in a metastasis already before vaccination, recognized an antigenic peptide presented by HLA-A2 molecules and encoded by a mutated sequence in the gene coding for Triad3A, an E3 ubiquitin-protein ligase. Analysis of DNA extracted from tumor cells of a metastasis suggests that about half of these cells do not carry the mutated Triad3 allele. This might contribute to explain the coexistence of tumor cells and CTL 10 within the metastasis.
- Affiliations
Citations
Corbière, V. (2006). Spécificité des lymphocytes T présents dans une tumeur humaine qui régresse après vaccination avec un antigène MAGE. https://hdl.handle.net/2078.5/112195