DiverDC: Understanding dendritic cell diversity with cell reprogramming

Cancer immunotherapy has changed the paradigm for cancer treatment, but the majority of patients do not respond. Non-responsiveness to checkpoint blockade could result from many causes, including failure of dendritic cell (DC) priming of CD8+ T cells. Indeed, checkpoint blockade efficacy has recently been shown to be dependent on the conventional type 1 subset of dendritic cells (cDC1). Recent studies have also highlighted a critical contribution of type 2 dendritic cells (cDC2s) and plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. In contrast, the regulatory program of a subset of DCs limits anti-tumor immunity. Understanding how this diversity of DCs is generated is crucial to both predict and promote response to checkpoint blockade and overall patient survival. The transcription factors (TFs) underlying the instruction of DC sub-programs remains poorly understood and hinders rational design for cancer immunotherapy. We were first to identify that enforced expression of PU.1, IRF8 and BATF3 induce cDC1-like cells from fibroblasts. An exciting opportunity for understanding DC lineage diversity emerges with direct cell reprogramming approaches. The purpose of the project is to uncover TF codes underlying DC diversity employing TF barcoding technologies at the single cell level. The project will be centered on testing the hypothesis that the combinatorial action of different TFs results in multiple DC subsets mirroring in vivo specification during development and specialization in tissues. This will contribute to understand the drivers of DC diversification and will allow us to focus on the generation of cDC2 and pDC from fibroblasts.