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Pereira Lab Publishes in Immunity: Decoding Transcription Factor Blueprints Behind Dendritic Cell Diversity
We are pleased to announce the publication of our latest article in Immunity, titled: “Anchored screening identifies transcription factor blueprints underlying dendritic cell diversity and subset-specific anti-tumor immunity.” In this study, the Pereira Lab presents a direct cell reprogramming approach to dissect the transcriptional logic behind dendritic cell (DC) diversity and to engineer subset-specific DCs with defined immunological functions. DCs are a heterogeneous family of antigen-presenting cells that play crucial roles in initiating and shaping anti-tumor immunity. They are traditionally divided into three main subsets: conventional DC type 1 (cDC1s), conventional DC type 2 (cDC2s), and plasmacytoid DCs (pDCs). While cDC1s are well known for their capacity to drive cytotoxic T cell responses and are associated with improved outcomes in many cancers, recent studies also suggest that cDC2s and pDCs contribute to anti-tumor immune responses, particularly in solid tumors such as breast cancer.
To explore the transcriptional programs that govern DC identity and function, we developed an anchored transcription factor (TF) screening strategy. This approach allowed us to systematically identify key TF combinations that could reprogram fibroblasts into distinct DC-like subsets. Through this screen, we found that the combination of PU.1, IRF4, and PRDM1 (referred to as PIP) induces a pro-inflammatory, cDC2B-like phenotype, which we termed iDC2s. In contrast, the combination of SPIB, IRF8, and IKZF2 (SII) gave rise to iLDCs, a population that resembles immature, lymphoid-leaning pDCs. Both combinations rely on an ETS + IRF pair (PU.1/IRF4 or SPIB/IRF8) to prime DC identity. The third factor (PRDM1 or IKZF2) directs the subtype-specific program in induced dendritic cells (iDCs).
Both iDC2s and iLDCs displayed distinct transcriptional and phenotypic profiles, including the expression of subset-specific surface markers. iDC2s expressed CLEC12A, SIRPα, CCR2, and CD32, aligning with the inflammatory cDC2B subset, and demonstrated a strong ability to take up antigens, process them, and cross-present to CD8+ T cells. iLDCs, on the other hand, showed expression of LY6C, CCR9, and B220, with a more immature yet pro-inflammatory profile. Interestingly, while iLDCs secreted low levels of type I interferons (IFN-I), co-expression of IRF4 with the SII module was sufficient to trigger IFN-β secretion.
To uncover the mechanisms underlying these reprogramming events, we performed chromatin immunoprecipitation sequencing (ChIP-seq) to track early TF binding. Each TF triad had different chromatin engagement modes and co-bound subset-specific genes early on, showing that DC subset divergence is set in motion at the very start of reprogramming.
The study then moved in vivo to test whether these reprogrammed DCs could functionally shape anti-tumor responses. Using two distinct tumor models—YUMM1.7 melanoma, which is highly responsive to cDC1-driven immunity, and EO771 breast cancer, which benefits from cDC2- and pDC-mediated responses—we demonstrated that DC subsets reprogrammed with specific TF combinations could elicit orthogonal anti-tumor effects. In YUMM1.7, reprogrammed iDC1s delayed tumor progression and extended survival, while in EO771, both iDC2s and iLDCs were effective at slowing tumor growth. Remarkably, mice treated with these reprogrammed DCs and later rechallenged with tumor cells remained tumor-free, suggesting the induction of long-term immune memory. Analysis of the tumor microenvironment (TME) revealed distinct immune cell infiltration and cytokine secretion patterns, supporting the idea that each DC subset contributes uniquely to shaping anti-tumor immunity.
This work, led by Luís Oliveira, Abigail Altman, and Ilia Kurochkin, along with Pereira Lab members Ervin Ascic, Evelyn Halitzki, Diogo Cabral, Malavika Sreekumar Nair, and Pedro Cunha, provides new insight into how transcription factors cooperate to establish DC identity and function. Our findings lay the groundwork for the tailored generation of DC subsets that could be harnessed for personalized cancer immunotherapy.
We are deeply grateful to our collaborators at Asgard Therapeutics, as well as the groups of Michael Kharas, Joan Yuan, and Katharina Lahl. This work was supported by the European Research Council (ERC), Horizon Europe, Cancerfonden, Swedish Research Council, Novo Nordisk Fonden, Cancer Research Institute, Knut and Alice Wallenberg Foundation, and FCT.
Click here to read the full article!
About the illustration
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.
