Location: Campus Drie Eiken, Promotiezaal, D.Q.002
Time: 13u - 16u
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1. Jöran Melis
Fundamental insights in the immunosuppressive metabolic effects of the hypoxic tumor microenvironment on natural killer cells in head and neck squamous cell carcinoma
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide, with a majority of the patients progressing towards recurrent/metastatic HNSCC with limited treatment options. Despite being a highly inflamed tumor type, characterized with a relatively high presence of natural killer (NK) cells, the hostile tumor microenvironment (TME) limits the effectiveness of immunotherapies, including newly developed adoptive cellular therapies in clinical trials. In this context, HNSCC is recognized as a hypoxic tumor, which also greatly influences the metabolic constitution of the TME. Therefore, I hypothesize that HNSCC cells secrete immunosuppressive metabolites in the TME, exaggerated by the high level of hypoxia, which induce evasion to NK cells.
In order to mimic the TME, I will implement physiologic and conditioned media at different oxygen levels. Metabolic and functional analyses will reveal and prioritize metabolite changes induced in media composition that affect NK cell function. Following in vitro validation, NK cell functionality will be assessed in vivo using an orthotopic humanized mouse model after restoration of NK cell cytotoxicity with standard-of-care HNSCC treatment. As such, the described project will obtain fundamental insights into the suppressive role of hypoxia-induced metabolites on NK cells and will provide valuable knowledge for adoptive cellular therapies in development.
2. Amber Driesen
Characterization of iron-chromatin dependent epigenetic regulation of ferroptosis therapy response in multiple myeloma
Multiple myeloma is a hematological cancer of the plasma cells, which is characterized by bone marrow end-organ damage. Although there are currently many conventional treatment strategies, these patients eventually relapse and develop apoptotic multi-drug resistance. Remarkably, the clonal expansion of these malignant plasma cells requires large amounts of iron to maintain their rapid growth and proliferation rate as compared to their healthy counterparts. Interestingly, this makes multiple myeloma vulnerable for iron-dependent cell death, called ferroptosis, as a new alternative treatment option to overcome therapy resistance.
Of particular interest, among various post-translational histone modifications identified by proteomic approaches in our lab, we were the first to identify iron-histone complexes during ferroptosis and for which no biological regulatory functions have yet been described. Therefore, in my PhD project, I aim to biochemically characterize the histone-iron interaction at the nucleosome level (1), as well as assess the functional role of iron-histone interactions in ferroptosis signaling in multiple myeloma cell lines (2). Ultimately I hope that my research fundamentally contributes to the better understanding of the ferroptosis therapy response, which could lead to novel possible (epigenetic) treatment options for MM patients.
3. Donovan Flumens - Laboratory of Experimental Hematology
Tumor Immunology GroupNon-viral T-cell engineering : The way forward
Genetic engineering of T cells for adoptive T-cell therapies has marked a turning point in personalized immunotherapy. Traditionally, T cells have been genetically engineered with viral vectors, posing a thread of insertional mutagenesis. Introduction of genes via non-insertional RNA electroporation, is an established versatile strategy that more recently has also been applied to introduce single guide RNAs within the CRISPR-associated system (Cas) system, one of the most powerful tools for specific and stable genome editing of primary human T cells. Non-viral methods that involve transient expression of Cas9, such as those using Cas9 ribonucleoproteins or Cas9 mRNA, benefit from a better safety profile compared to stable methods that raise concerns about persistent Cas9 expression and resulting off-target editing. With a focus on the development of safer and fitter T-cell therapies, electroporation of the CRISPR/Cas9 system can be exploited to stably knockout the complete native T-cell receptor or as an unprecedented tool to re-write targeted genome sequences using homology directed repair. Knocking out the native TCR avoids TCR mispairing between native and introduced TCRs and prevents graft-versus-host disease in allogeneic T-cell therapies. Taking it one step further, T cells can be redirected at the same time by replacing the native TCR genes with tumor-specific CAR or TCR sequences using CRISPR knockin. In summary, non-viral single-electroporation CRISPR/Cas9 editing strategies provide a promising versatile platform for rapid multiplex genome engineering of primary human T cells.