The histone deacetylase HDAC1 controls dendritic cell development and anti-tumor immunity
Cristiano De Sá Fernandes,
Philipp Novoszel,
Tommaso Gastaldi,
Dana Krauß,
Magdalena Lang,
Ramona Rica,
Ana P. Kutschat,
Martin Holcmann,
Wilfried Ellmeier,
Davide Seruggia,
Herbert Strobl,
Maria Sibilia
Affiliations
Cristiano De Sá Fernandes
Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
Philipp Novoszel
Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
Tommaso Gastaldi
Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
Dana Krauß
Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
Magdalena Lang
Division of Immunology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
Ramona Rica
Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
Ana P. Kutschat
St. Anna Children’s Cancer Research Institute, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
Martin Holcmann
Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
Wilfried Ellmeier
Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
Davide Seruggia
St. Anna Children’s Cancer Research Institute, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
Herbert Strobl
Division of Immunology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
Maria Sibilia
Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria; Corresponding author
Summary: Dendritic cell (DC) progenitors adapt their transcriptional program during development, generating different subsets. How chromatin modifications modulate these processes is unclear. Here, we investigate the impact of histone deacetylation on DCs by genetically deleting histone deacetylase 1 (HDAC1) or HDAC2 in hematopoietic progenitors and CD11c-expressing cells. While HDAC2 is not critical for DC development, HDAC1 deletion impairs pro-pDC and mature pDC generation and affects ESAM+cDC2 differentiation from tDCs and pre-cDC2s, whereas cDC1s are unchanged. HDAC1 knockdown in human hematopoietic cells also impairs cDC2 development, highlighting its crucial role across species. Multi-omics analyses reveal that HDAC1 controls expression, chromatin accessibility, and histone acetylation of the transcription factors IRF4, IRF8, and SPIB required for efficient development of cDC2 subsets. Without HDAC1, DCs switch immunologically, enhancing tumor surveillance through increased cDC1 maturation and interleukin-12 production, driving T helper 1-mediated immunity and CD8+ T cell recruitment. Our study reveals the importance of histone acetylation in DC development and anti-tumor immunity, suggesting DC-targeted therapeutic strategies for immuno-oncology.
