| Project Detail |
Molecular insight into the failure of dendritic cell vaccines in leukemia
Dendritic cells (DCs) are the professional antigen-presenting cells of the immune system, promoting T cell immune responses against specific antigens. These properties have led to the development of DC based vaccines for the treatment of chronic lymphocytic leukemia (CLL). However, clinical evidence has been disappointing, suggesting a more in-depth investigation of the immune suppression mechanisms in CLL. Funded by the Marie Sklodowska-Curie Actions programme, the engineereD to Clear project aims to understand why DC vaccines fail. The work will focus on interleukin-4-induced 1 enzyme, which downregulates the function of CD8+ T cells. Results will help take current DC vaccines into the next era.
Chronic lymphocytic leukemia is a common leukemia in adults characterized by an extremely immune suppressive microenvironment, which leads to the failure of otherwise effective immunotherapy regimens including dendritic cell (DC) based tumor vaccines. Recent attempts to understand immune suppression in CLL provided substantial evidence and identified that over-expression of amino acid catabolizing enzyme interleukin-4-induced 1 (IL4i1) in CLL and immune cells as key phenomenon in CLL mediated immune suppression. IL4i1 is secreted by DCs in the immune synapse and downregulates CD8+ T cell effector functions while presenting antigens, which perfectly explains failure of DC vaccines in CLL treatment. Addressing this, the important objectives of the present project are 1. To investigate the negative impacts of IL4i1 on DC functions, which are in particular relevance to DC vaccines and 2. To analyze the potential of IL4i1 deficient DCs in CLL vaccination. In this project I will first study ex vivo the DC and CD8+ T cell dysfunctions associated with DC secreted IL4i1 by assessing antigen presentation, immune synapse formation, CD8+ T cell activation and proliferation using both model antigen SIINFEKL and whole CLL cell antigens. Next, I will feed IL4i1 deficient DCs with whole CLL cell antigens and study using cutting-edge techniques their potential in eliciting anti-CLL immune responses in vivo using Eµ-TCL1 adaptively transferred CLL mouse model (TCL1AT).
I obtained my PhD in 2021 and presently working as research associate at the department of Biochemistry and Molecular Biology, University of Szeged, Hungary. I propose this project for Marie Curie postdoctoral fellowship- European fellowships. This project will be carried out in the division of Molecular Genetics, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Heidelberg, Germany under the supervision of Dr. Martina Seiffert. |
