Journal Article

DKFZ-2025-00675

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Senescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control.

Belenki, D. ; Richter-Pechanska, P. ; Shao, Z. ; Bhattacharya, A. ; Lau, A. ; Nabuco Leva Ferreira de Freitas, J. A. ; Kandler, G. ; Hick, T. P. ; Cai, X. ; Scharnagl, E. ; Bittner, A. ; Schönlein, M. ; Kase, J. ; Pardon, K. ; Brzezicha, B. ; Thiessen, N. ; Bischof, O. ; Dörr, J. R. ; Reimann, M. ; Milanovic, M.DKFZ* ; Du, J. ; Yu, Y. ; Chapuy, B. ; Lee, S. ; Leser, U. ; Scheidereit, C. ; Wolf, J. ; Fan, D. N. Y.DKFZ* ; Schmitt, C. A.DKFZ*

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-57429-x

Abstract: 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.

Keyword(s): Animals (MeSH) ; Humans (MeSH) ; Cellular Senescence: immunology (MeSH) ; Cellular Senescence: genetics (MeSH) ; Mice (MeSH) ; T-Lymphocytes: immunology (MeSH) ; Cell Lineage (MeSH) ; Cell Differentiation (MeSH) ; Dendritic Cells: immunology (MeSH) ; Cell Line, Tumor (MeSH) ; Lymphoma, Large B-Cell, Diffuse: immunology (MeSH) ; Lymphoma, Large B-Cell, Diffuse: genetics (MeSH) ; Lymphoma, Large B-Cell, Diffuse: pathology (MeSH) ; Proto-Oncogene Proteins: metabolism (MeSH) ; Proto-Oncogene Proteins: genetics (MeSH) ; CCAAT-Enhancer-Binding Protein-beta: metabolism (MeSH) ; CCAAT-Enhancer-Binding Protein-beta: genetics (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Cell Plasticity (MeSH) ; Transcription Factor AP-1: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Monocytes: immunology (MeSH) ; Monocytes: metabolism (MeSH) ; Lymphoma, B-Cell: immunology (MeSH) ; Lymphoma, B-Cell: genetics (MeSH) ; Female (MeSH) ; Transcription Factors: metabolism (MeSH) ; Transcription Factors: genetics (MeSH) ; Trans-Activators (MeSH) ; proto-oncogene protein Spi-1 ; Proto-Oncogene Proteins ; CCAAT-Enhancer-Binding Protein-beta ; Transcription Factor AP-1 ; Transcription Factors ; Trans-Activators

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Berlin (BE01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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