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CLECT-X Sintesi della relazione

Project ID: 9205
Finanziato nell'ambito di: FP6-MOBILITY
Paese: United Kingdom

Final Activity Report Summary - CLECT-X (Functional characterisation of a novel C-type lectin receptor differentially expressed in CD8alpha+ dendritic cells)

We found a novel dendritic cell (DC) receptor that could be used for tumour therapy. Strategies to vaccinate cancer patients against their own tumour cells were pursued for many years, albeit with limited success. We described a novel surface receptor which was expressed on a specific subset of DCs and showed that a powerful anti-tumour immune response could be induced by targeting this receptor with tumour-derived antigen fragments.

DCs, the 'professional antigen presenting cells' of the immune system, are versatile controllers of T-lymphocyte responses. In mice, the CD8a+ subset of DCs have been shown to be particularly effective in 'cross presentation', a process whereby extracellular antigens are captured and processed for display on major histocompatibility complex (MHC) class I receptor molecules. Since MHC class I presentation is required for the induction of cytotoxic T-lymphocytes (CTLs) and a robust CTL response aimed at tumour antigens could be effective in tumour killing, CD8a+ DCs are attractive candidates for tumour immunotherapy.

The presentation of specific tumour antigens on CD8a+ DCs could be achieved by coupling the antigen to antibodies targeted to cell surface receptors. The obstacle in this approach had been the identification of a surface receptor with a sufficiently narrow expression range. By carrying out a representational difference analysis of freshly isolated CD8a+ versus CD8a- DCs, the authors identified a previously unknown type II transmembrane receptor of the C-type lectin family, which was named DC, NK lectin group receptor 1 (DNGR-1). Subsequent analysis using specific antibodies confirmed the receptor's almost exclusive expression on CD8a+ DCs, while a much lower level of expression was also found on plasmacytoid DCs, and showed that antibody-bound receptor was efficiently internalised. In vivo delivery of antigen covalently coupled to the antibody resulted in antigen cross presentation by CD8+ DCs, and when administered together with adjuvants a potent CTL response could be induced.

The potential of this system for tumour therapy was demonstrated in the B16 melanoma model, a poorly immunogenic mouse tumour that was difficult to treat. A single administration of tumour antigen conjugated to anti-DNGR-1 plus adjuvant proved sufficient to break tolerance to self, inducing CTL priming and B16 eradication. Antigen coupled to control antibodies plus adjuvant or targeting of antigen to DNGR-1 in the absence of adjuvant did not induce an immune response.

In humans, the expression of DNGR-1 was restricted to a small subset of DCs that bore similarities to mouse CD8a+ DCs and, just like its mouse ortholog, it functioned as an endocytotic receptor. It remained to be determined whether human DNGR-1+ DCs were indeed the long-sought after equivalent of mouse CD8a+ DCs, which would make DNGR-1 a particularly exciting target for human cancer immunotherapy.


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