Lehrstuhl für Haut- und Geschlechtskrankheiten
Josef-Schneider-Str. 2, 97080Wuerzburg
Other participating persons and organisations:
Research foci (and basic equipment-based research projects):
Characterization and modulation of the cellular immune response against melanoma
In one of our projects we were able to cure mice suffering from melanoma through the treatment with a recombinant antibody-lymphotoxin-alpha fusion protein. This therapy induced the formation of a lymphoid-like tissue in the tumor microenvironment containing L-selectin+ T cells, MHC class II+ antigen presenting cells as well as B and T cell aggregates. Furthermore, possible entry channels for naive T cells, i.e., PNAd+/TCA4+ high endothelial venules, were observed. Although only slight over-expressions in some of the VB families for the TCR were detected, there was an increase of T cell clones among the tumor infiltrating T cells over the course of therapy. Moreover, the tumor infiltrating T cells were reactive against melanoma cells and the TRP-2180-188 peptide. Thus, through the lymphotoxin-alpha fusion protein a lymphoid-like tissue may be induced at the tumor site which subsequently can recruit, prime and expand naive T cells.
Another investigation dealt with the immunologic reactions at the vaccination site of melanoma patients. This model was used as the situation in therapeutic DC-based vaccinations used to treat human cancer differs substantially from the physiological scenario as only a small fraction of intradermally injected DC migrate to the draining lymph node and the majority of cells remain at the site of inoculation leaving mature DC at the skin. These sites were characterized by a distinct oligoclonal T cell infiltrate comprising both L-Selectin+/CD45RA+ and L-Selectin+/CD45RA cells. PNAd expressing blood vessels represent possible entry channels for such naive and central memory T cells, the former are likely attracted by DC-CK1 produced by the injected DC. In situ staining with multimeric peptide/MHC class I complexes revealed that infiltrating T cells specifically recognize peptide epitopes presented by the injected DC. Thus, the fraction of DC not migrating to secondary lymphatic tissue after therapeutic inoculation nevertheless seem to be involved in a specific immune modulation.
Another project analyzed the T cell repertoire usage in multiple metastases of melanoma patients under therapie. As immune therapy for melanoma largely relies on preexisting T cell responses and recent reports demonstrated the localized nature of such responses, we characterized the effect of immune therapy on the distribution of clonotypic T cells. To this end, we analyzed the T cell receptor repertoire of multiple metastases of differentially treated melanoma patients revealing oligoclonal T cell responses and the occurrence of identical T cell clones in several metastases. These findings were, however, not limited to immune therapy, but were also observed after chemotherapy, suggesting its similar impact on the distribution of T cells.
Rewards and prizes:
1999 Posteraward of the Arbeitsgemeinschaft Dermatologische Onkologie;
2000 Merit Award of the American Society of Clinical Oncology;
2001 Posteraward of the Arbeitsgemeinschaft Dermatologische Forschung;
2001 German Skincancer award of the Arbeitsgemeinschaft Dermatologische Onkologie
DGGE setup for clonotype mapping of T cells;