Anchored screening identifies transcription factor blueprints underlying dendritic cell diversity and subset-specific anti-tumor immunity

Highlights

• Anchored screening identifies ETS-IRF pairs and a third factor specifying DC subsets
• PU.1, IRF4, and PRDM1 induce a pro-inflammatory cDC2B-like identity
• SPIB, IRF8, and IKZF2 drive an immature lymphoid pDC-like program
• Induced DC subsets trigger anti-tumor responses and durable immunological memory

Summary

Transcription factor cooperation is essential for specifying the heterogeneous dendritic cell (DC) lineages that orchestrate adaptive immunity, yet how it drives subset diversification remains poorly understood. Here, we employed a sequential anchored screen of 70 transcription factors using direct cellular reprogramming to identify regulators that specify type 2 conventional DCs (cDC2s) and plasmacytoid DCs (pDCs). We identified PU.1, IRF4, and PRDM1 as inducers of a pro-inflammatory cDC2B-like fate and SPIB, IRF8, and IKZF2 as mediators of an immature lymphoid DC program. Transcriptomic profiling linked these triads to lineage-specific signatures and demonstrated their requirement for subset identity. Mechanistically, lineage divergence was driven by chromatin co-engagement at subset-specific sites early in reprogramming. Functionally, reprogrammed DCs employed distinct immune mechanisms to elicit orthogonal anti-tumor responses in different tumor models. Collectively, our findings uncover transcriptional circuits that control DC diversification and pave the way to generate patient-tailored DC subsets for cancer immunotherapy.

Cover design credit: Avesta Rastan

Casting for Dendritic Cell Diversity – About the Cover

In this issue, Henriques-Oliveira et al. employ a direct cellular-repogramming-sequential anchored screen of 70 transcription factors to examine the transcription factor cooperativity that specifies distinct dendritic cell (DC) lineages. The authors identify transcriptional regulators of type 2 conventional DCs and plasmacytoid DCs and demonstrate distinct functions for these cells in anti-tumor immunity. The screen is depicted as a fishing net hauling distinct fish (DCs) from waters full of various immune cells as well as hidden tumor threats. Illustration by Avesta Rastan.

Web-Based Application for Data

https://cellreprolab.shinyapps.io/diverse_DC_atlas

Initial Illustration for Press Releases

Mapping the Routes to DC Identity and anti-tumor immunity

In a barren immune desert, three reprogramming paths guided by transcription factor combinations PIB, PIP, and SII, converge on a lush oasis symbolizing effective anti-tumor immunity. Henriques-Oliveira, Altman, and Kurochkin et al. show how unique cell reprogramming routes give rise to functionally diverse dendritic cell subsets, trailing new paths for immunotherapy.
Illustration by Avesta Rastan.