Anchored screening identifies transcription factor blueprints underlying dendritic cell diversity and subset-specific anti-tumor immunity
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.
Authors
- Evelyn Halitzki (ORCID: https://orcid.org/0000-0002-5804-4837)
- Ervin Ascic (ORCID: https://orcid.org/0000-0002-3839-0572)
- Carlos‐Filipe Pereira (ORCID: https://orcid.org/0000-0002-9724-1382)
- M. Nair (ORCID: https://orcid.org/0000-0003-1378-7247)
- Stefano Vergani (ORCID: https://orcid.org/0000-0003-0524-5093)
- Isabel Ulmert (ORCID: https://orcid.org/0000-0003-1908-4913)
- Ilia Kurochkin (ORCID: https://orcid.org/0000-0003-3100-0903)
- Fábio F. Rosa (ORCID: https://orcid.org/0000-0002-7714-5852)
- Abigail Altman (ORCID: https://orcid.org/0009-0002-9692-2976)
- Alexandru‐Emil Matei (ORCID: https://orcid.org/0000-0003-1248-3145)
- Michael G. Kharas (ORCID: https://orcid.org/0000-0002-1165-6991)
- Luís Henriques‐Oliveira (ORCID: https://orcid.org/0000-0002-6937-7047)
- Joan Yuan (ORCID: https://orcid.org/0000-0001-9129-8356)
- Cristiana F. Pires (ORCID: https://orcid.org/0000-0003-2985-6323)
- Katharina Lahl (ORCID: https://orcid.org/0000-0003-4919-331X)
- Signe Holst (ORCID: https://orcid.org/0000-0002-8617-7194)
- Sun‐Mi Park
- Pedro P. Cunha
- Diogo Pértiga-Cabral
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- University of Calgary (CA)
- Lund University (SE)
- Medicon Village (SE)
- University of Coimbra (PT)
- Technical University of Denmark (DK)
Publication Details
- Journal
- Immunity
- Published
- 2025-08-29
- DOI
- https://doi.org/10.1016/j.immuni.2025.08.001
- Citations
- 4
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- article
- Field-Weighted Citation Impact
- 3.19
Funders
- Cancer Research Institute
- Francis Crick Institute
- European Commission
- Cancerfonden
- Lunds Universitet
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Science for Life Laboratory
- Novo Nordisk Fonden
- University at Buffalo
- Fundação para a Ciência e a Tecnologia