Generating Dendritic Cells by Direct Cell Reprograming

Cancer immunotherapy employs components of a persons’ immune system to fight cancer. Some of these therapies rely on Dendritic Cells (DCs), specialized in recognition, processing and presentation of antigens to immune effector cells. Current strategies to isolate mature DCs from cancer patients have met limited success. Direct cell reprogramming offers an exciting alternative as the identity of a healthy cell can be modified with lineage instructive transcription factors (TFs).We propose to generate autologous antigen-presenting DCs in vitro through direct lineage reprogramming of fibroblasts. Our first aim is to identify DC-inducing TFs using mouse fibroblasts harboring a DC-specific reporter. This analysis will be complemented with immunophenotipic and transcriptional characterization to confer their similarity with “natural” DCs. We will then assess the functional proprieties of DCs using both in vitro and in vivo assays. In our second aim, we will assess whether the identified combination of TFs can reprogram human dermal fibroblasts into DCs. Their ability to efficiently present antigens and to mount an immune response against cancer cells will be tested.Collectively this work will provide thorough insight into DC transcriptional networks. This knowledge will be applied for patient-specific DC generation. Ultimately, this project will represent a pioneering contribution for applying direct reprogramming for inducing immunity and generating novel immunotherapies.