engineereD to Clear · Investigation on the vaccination potential of IL4i1 deficient dendritic cells in Chronic lymphocytic leukemia
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2022-10-01 → 2024-09-30
- EU contribution
- €189,687
- Participants
- 1
- Scheme
- HORIZON-TMA-MSCA-PF-EF
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Results in brief
Investigation on the vaccination potential of IL4i1 deficient dendritic cells in Chronic lymphocytic leukemia
The primary objective of this project is to enhance the efficacy of dendritic cell (DC)-based immunotherapy by targeting the Il4i1 metabolic immune checkpoint. Chronic Lymphocytic Leukemia (CLL) presents unique immunosuppressive challenges, making it imperative to identify and harness mechanisms that can reinvigorate immune responses. The project explores whether Il4i1-knockout (KO) dendritic cells, which demonstrate superior antigen presentation, T-cell activation, and migration capacities, can serve as an advanced therapeutic tool. Our approach involves differentiating Il4i1-WT and Il4i1-KO conventional dendritic cells (cDC1s) from mouse bone marrow to evaluate their functional improvements. Key assays include antigen presentation and migration studies, OT-1 T-cell proliferation, and in vivo tracking of DC migration. Additionally, integrating mass spectrometry-based immunopeptidomics aims to identify hTCL1A peptides for DC feeding, offering potential avenues for a vaccine strategy within the TCL1-AT mouse model of CLL. The project's impacts are twofold: First, it addresses the unmet need for more effective DC-based therapies, particularly in the context of CLL's complex immune evasion tactics. Second, by leveraging the increased immunogenicity of Il4i1-KO DCs, the findings could inform broader applications in immunotherapy for various cancers. Given the strategic importance of advancing cancer immunotherapy, these results are poised to contribute significantly to the field, with potential translational outcomes impacting clinical practices. This project's significance lies in its innovative focus on Il4i1 as a metabolic immune checkpoint and the scale of its expected impact, which includes improving survival rates, reducing relapse, and setting a precedent for next-generation immunotherapies.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG · HeidelbergCoordinatorGermany
Links
- View on CORDIS
- DOI: 10.3030/101066882
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5189ecdfc&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5fa856e3d&appId=PPGMS
Data: CORDIS, © European Union