Caractérisation de la réponse T anti-vaccinale chez des patients atteints de mélanome
(2012)
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- Authors
- Supervisors
- van der Bruggen, Pierre
- Abstract
- (en) A number of therapeutic vaccines have been evaluated in patients with metastatic melanoma. Tumor regressions were observed in 20% of the vaccinated patients. Complete and long-term clinical responses have been occasionally observed. Some researchers have used autologous dendritic cells loaded with antigenic peptides to immunize patients, because dendritic cells are considered very effective in antigen presentation to T cells. A first objective of our work was to evaluate the anti-vaccine CTL responses in several patients vaccinated with dendritic cells loaded with antigens derived from the protein MAGE-3. The vaccine was able to induce a response in four of the five analyzed patients. This response was polyclonal in three of the four responding patients. The frequencies of anti-vaccine CTL ranged from 1/1 000 to 1/100 000 of blood CD8 T cells. While these responses were generally low, they seemed to be associated with tumor regressions. In one patient, we were able to extend our analysis beyond the anti-vaccine CTL response and we analyzed the T cell response directed against various antigens expressed by the tumor. We identified a CTL clone directed against one of these antigens. This antigen was previously unknown and derived from protein MAGE-C2. The frequency of anti-MAGE-C2 CTL in the blood increased after vaccination. Unlike the anti-vaccine CTL, this CTL clonotype was found to accumulate in cutaneous metastases. It is tempting to think that it played an important role in the regression of some of these metastases. We also decided to examine the functional profiles of the anti-vaccine CTL that were isolated from the blood of patients. Since many publications associate the expression of several surface markers with a functional differentiation status of T cells, we analyzed the phenotype of the anti-vaccine CTL clones using differentiation markers described in the literature, namely CCR7 and CD45RA. All the analysed clones had lost the expression of CCR7, and some of them strongly expressed CD45RA. In contradiction with published differentiation models, those CCR7-/CD45RA+ clones did not seem to have reached a terminally differentiated status, as they kept important proliferative capacities. Our observations revealing cyclic variations of CD45RA expression depending on the antigenic contacts, we propose that CD45RA re-expression on CCR7- CD8 T cells is a consequence of a prolonged lack of antigenic contact rather than the sign of a terminal differentiation.
- Affiliations
Citations
Carrasco Bertrand, J. (2012). Caractérisation de la réponse T anti-vaccinale chez des patients atteints de mélanome. https://hdl.handle.net/2078.5/161040