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.
