Senescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control
Cellular senescence is a stress-inducible state switch relevant in aging, tumorigenesis and cancer therapy. Beyond a lasting arrest, senescent cells are characterized by profound chromatin remodeling and transcriptional reprogramming. We show here myeloid-skewed aberrant lineage plasticity and its immunological ramifications in therapy-induced senescence (TIS) of primary human and murine B-cell lymphoma. We find myeloid transcription factor (TF) networks, specifically AP-1-, C/EBPβ- and PU.1-governed transcriptional programs, enriched in TIS but not in equally chemotherapy-exposed senescence-incapable cancer cells. Dependent on these master TF, TIS lymphoma cells adopt a lineage-promiscuous state with properties of monocytic-dendritic cell (DC) differentiation. TIS lymphoma cells are preferentially lysed by T-cells in vitro, and mice harboring DC-skewed Eμ-myc lymphoma experience significantly longer tumor-free survival. Consistently, superior long-term outcome is also achieved in diffuse large B-cell lymphoma patients with high expression of a TIS-related DC signature. In essence, these data demonstrate a therapeutically exploitable, prognostically favorable immunogenic role of senescence-dependent aberrant myeloid plasticity in B-cell lymphoma.
Authors
- Maurice Reimann (ORCID: https://orcid.org/0000-0002-7876-0128)
- Jana Wolf (ORCID: https://orcid.org/0000-0003-3254-5868)
- Yong Yu (ORCID: https://orcid.org/0000-0003-1928-2514)
- Soyoung Lee (ORCID: https://orcid.org/0000-0002-4614-2931)
- Nina Thiessen
- Animesh Bhattacharya (ORCID: https://orcid.org/0000-0003-3733-7670)
- Claus Scheidereit (ORCID: https://orcid.org/0000-0002-0446-6129)
- Andrea Lau
- Paulina Richter‐Pechańska (ORCID: https://orcid.org/0000-0001-6727-6317)
- Xiurong Cai (ORCID: https://orcid.org/0000-0002-6937-3708)
- Dorothy Ngo-Yin Fan
- Clemens A. Schmitt (ORCID: https://orcid.org/0000-0002-4731-2226)
- Jing Du
- Dimitri Belenki (ORCID: https://orcid.org/0000-0002-9004-9849)
- Aitomi Bittner (ORCID: https://orcid.org/0000-0001-6434-0950)
- Ulf Leser (ORCID: https://orcid.org/0000-0003-2166-9582)
- Zewei Shao (ORCID: https://orcid.org/0000-0002-8748-0638)
- Katharina Pardon (ORCID: https://orcid.org/0009-0001-5048-3261)
- Oliver Bischof (ORCID: https://orcid.org/0000-0003-2422-6277)
- Timon Hick (ORCID: https://orcid.org/0000-0002-9777-6635)
- Martin Schönlein (ORCID: https://orcid.org/0000-0002-1010-0975)
- Bjoern Chapuy (ORCID: https://orcid.org/0000-0002-6485-8773)
- José Américo Nabuco Leva Ferreira de Freitas (ORCID: https://orcid.org/0000-0003-3689-765X)
- Jan R. Dörr (ORCID: https://orcid.org/0000-0002-4927-6548)
- Maja Milanovic (ORCID: https://orcid.org/0000-0003-1860-6003)
- Bernadette Brzezicha
- Julia Kase
- Eva Scharnagl
- Gregor Kandler
Institutions
- Johannes Kepler University of Linz (AT)
- Binzhou Medical University (CN)
- Shandong University of Aeronautics (CN)
- Inserm (FR)
- Universität Hamburg (DE)
- Research Institute of Molecular Pathology (AT)
- Université Paris-Est Créteil (FR)
- Max Delbrück Center (DE)
- Humboldt-Universität zu Berlin (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Kepler Universitätsklinikum (AT)
- German Marine Research Consortium (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Institut Mondor de Recherche Biomédicale (FR)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-31
- DOI
- https://doi.org/10.1038/s41467-025-57429-x
- Citations
- 6
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 4.78
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Bundesministerium für Gesundheit
- Deutsche Krebshilfe