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

Henriques-Oliveira, Luís LU ; Altman, Abigail R. LU orcid ; Kurochkin, Ilia LU ; Ascic, Ervin LU orcid ; Halitzki, Evelyn LU ; Matei, Andreea Medeea LU ; Pértiga-Cabral, Diogo LU ; Ulmert, Isabel ; Holst, Signe and Nair, Malavika Sreekumar LU , et al. (2025) In Immunity 58(10). p.13-2438
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
anti-tumor immunity, cDC2, cellular reprogramming, dendritic cells, IKZF2, IRF4, IRF8, pDC, PRDM1, transcription factor cooperation
in
Immunity
volume
58
issue
10
pages
13 - 2438
publisher
Cell Press
external identifiers
  • scopus:105016822888
  • pmid:40885192
ISSN
1074-7613
DOI
10.1016/j.immuni.2025.08.001
language
English
LU publication?
yes
id
b6c0374d-1f90-4b3c-a6eb-9687995e0686
date added to LUP
2025-11-24 14:49:07
date last changed
2025-11-25 03:34:31
@article{b6c0374d-1f90-4b3c-a6eb-9687995e0686,
  abstract     = {{<p>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.</p>}},
  author       = {{Henriques-Oliveira, Luís and Altman, Abigail R. and Kurochkin, Ilia and Ascic, Ervin and Halitzki, Evelyn and Matei, Andreea Medeea and Pértiga-Cabral, Diogo and Ulmert, Isabel and Holst, Signe and Nair, Malavika Sreekumar and Cunha, Pedro P. and Park, Sun Mi and Vergani, Stefano and Kharas, Michael G. and Yuan, Joan and Lahl, Katharina and Rosa, Fábio F. and Pires, Cristiana F. and Pereira, Carlos Filipe}},
  issn         = {{1074-7613}},
  keywords     = {{anti-tumor immunity; cDC2; cellular reprogramming; dendritic cells; IKZF2; IRF4; IRF8; pDC; PRDM1; transcription factor cooperation}},
  language     = {{eng}},
  number       = {{10}},
  pages        = {{13--2438}},
  publisher    = {{Cell Press}},
  series       = {{Immunity}},
  title        = {{Anchored screening identifies transcription factor blueprints underlying dendritic cell diversity and subset-specific anti-tumor immunity}},
  url          = {{http://dx.doi.org/10.1016/j.immuni.2025.08.001}},
  doi          = {{10.1016/j.immuni.2025.08.001}},
  volume       = {{58}},
  year         = {{2025}},
}