Improving dendritic cell-targeting cancer vaccination; a tale of mice and men
Sjoerd T.T. Schetters*, Laura Kruijssen, Matheus H.W. Crommentuijn, Hakan Kalay, Joke den Haan, Juan J. Garcia-Vallejo, Yvette van Kooyk
Department of Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, The Netherlands
Antigenic vaccination strategies against tumors and pathogens are often limited by their ability to reach the immune cell of interest, most often the dendritic cell (DC). We have improved the delivery by targeting antigen formulations to the C-type lectin, DC-SIGN, expressed on dendritic cells that further enhance antigen processing strengthening the initiation of protective adaptive immune responses. To accomplish DC delivery, we either conjugate the antigen to a DC-SIGN targeting antibody or by its natural ligand, the carbohydrate Lewis Y. Previously we have shown that targeting whole protein to DC-SIGN can lead to long-term tumor regression in combination therapy. We here analyzed in parallel, the efficacy of synthetic antigen peptides and -matrices with mouse DC-SIGN and human DC-SIGN targeting features to initiate antigen-specific immune responses in vitro, as well as in vivo. In vitro, antibodies targeting mouse and human DC-SIGN are able to deliver antigen for presentation on MHC class I and II and synthetic antigen-matrices decorated with Lewis Y mainly bind human DC-SIGN for antigen presentation. Both the antibody and Lewis Y targeting strategy enhance antigen-specific immune responses in hDC-SIGN transgenic mice after vaccination. We furthermore aimed to boost the immune responses by attracting DC-SIGN+ monocyte-derived dendritic cells (MoDC) to the vaccination site by preconditioning with MF59, the MoDC-attracting adjuvant used in current flu vaccines. Interestingly, preconditioning of the vaccination site had a differential effect on the immune response when antibody targeting strategies or whole protein vaccination, was used. Using advanced flow-cytometry analysis we identified that the quality of the CD8+ T cell population changed independent of the quantity of the antigen-specific immune response after preconditioning of the vaccination site. Hence our study shows that DC-SIGN targeting vaccines improve anti-tumor responses and that preconditioning of the vaccination site may have a great impact on the quality of the tumor specific T cell response.
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