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Agenda. februari 2018 tot 23-02-2019



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    Seminar Immunology

    “A mass spectrometry approach for epitope identification on the target cell – applied for therapeutic HPV vaccine design" by Angelika B. Riemer MD, Ph.D.

    For rational therapeutic vaccine design, detailed knowledge about target epitopes that are truly presented on cancer cells is essential. Many potential tumor-specific epitopes, such as viral epitopes or mutation-derived neoepitopes, are presented at low abundance. Thus, detection of these epitopes remains a challenge. We have developed a high-sensitivity targeted mass spectrometry (MS) approach for direct detection of low-abundant epitopes. We used human papillomavirus (HPV) as a model system, as high-risk HPVs cause over 600,000 cervical, anogenital and oropharyngeal cancer cases per year. Moreover, the HPV oncoproteins E6 and E7 are essential for the induction and maintenance of the malignant phenotype, and thus are ideal targets for immunotherapy.
    Potential HPV16 E6 and E7 target epitopes were predicted in silico and their HLA-binding verified in cellular binding assays. HLA-peptide complexes were immunoprecipitated from HPV16-positive cancer cells and the purified peptides were analyzed by MS. Identified HPV epitopes were assessed for immunogenicity in vitro with PBMC from healthy donors and in vivo in the MHC-humanized mouse model A2.DR1.
    The binding assays resulted in the identification of known and novel HPV16-derived HLA-binding peptides. Furthermore, we used this data to formulate rules on how to optimally use epitope prediction tools to increase the chances of predicting true HLA ligands. 14 HLA-A2-restricted HPV16 epitopes were detected on the surface of CaSki and 866 cervical cancer cells, 9 of which were novel. 13 out of the 14 MS-detected peptides were immunogenic in ELISpot assays. Vaccination of A2.DR1 mice with one selected epitope induced high numbers of specific cytotoxic T-cells, and caused anti-tumor effects in a newly developed HPV16 E6/E7-expressing A2.DR1-compatible tumor model.
    We conclude that our epitope detection and validation approach is suitable for validating even low-abundant candidate epitopes to be true immunotherapy targets. MS-detection of epitopes appears to be a good predictor of immunogenicity, which makes this approach an attractive platform for determining target epitopes for therapeutic cancer vaccines.

    Evenement

    15 maart 2018
    16:00 - 17:00 uur

    Na-1202k

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    Seminar Immunology

    “Subsets and T cell differentiation in chronic LCMV infection” by Dietmar Zehn MD, Ph.D.

    Failure to clear an infection can coincide with the appearance of T cells which express low amounts of cytokines and high levels of inhibitory receptors (PD-1, Lag-3, Tim-3). This phenotype has so far been viewed to mark exhausted and terminally differentiated effector cells. Nonetheless, “exhausted” T cell populations in chronic infections and tumors are long-living and can be expanded upon blocking inhibitory receptor ligand systems. This raised the questions how these populations are maintained and which mechanisms act in case of therapeutically induced re-expansion.
    We and others identified recently that both long-term T cell maintenance in chronic infections and re-expansion following blockade of PD-1 signaling are depending on a small subpopulation of T cells, which express the transcription factor Tcf-1. We showed that Tcf-1 positive T cells share key features with conventional memory T cells while they co-express markers of “exhausted T cells” (i.e. PD-1). These memory-like T cells are capable of undergoing self-renewal while they are continuously generating terminally differentiated effector cells. Given the presumed central role of the memory-like population for therapeutic purposes, we will report recent advances on molecules and mechanisms that control size and function of this subset.

    Evenement

    6 april 2018
    16:00 - 17:00 uur

    Na-1202k

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