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| Item Type: | Article |
|---|---|
| Title: | Senescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control |
| Creators: |
Belenki, D.  ORCID: https://orcid.org/0000-0002-9004-9849, Richter-Pechanska, P. ORCID: https://orcid.org/0000-0001-6727-6317, Shao, Z., Bhattacharya, A. ORCID: https://orcid.org/0000-0003-3733-7670, Lau, A., de Freitas, J.A.N.L.F. ORCID: https://orcid.org/0000-0003-3689-765X, Kandler, G., Hick, T.P., Cai, X., Scharnagl, Eva, Bittner, A. ORCID: https://orcid.org/0000-0001-6434-0950, Schönlein, M., Kase, J., Pardon, K., Brzezicha, B., Thiessen, N., Bischof, O. ORCID: https://orcid.org/0000-0003-2422-6277, Dörr, J.R. ORCID: https://orcid.org/0000-0002-4927-6548, Reimann, M. ORCID: https://orcid.org/0000-0002-7876-0128, Milanovic, M. ORCID: https://orcid.org/0000-0003-1860-6003, Du, J., Yu, Y. ORCID: https://orcid.org/0000-0003-1928-2514, Chapuy, B. ORCID: https://orcid.org/0000-0002-6485-8773, Lee, S. ORCID: https://orcid.org/0000-0002-4614-2931, Leser, U., Scheidereit, C. ORCID: https://orcid.org/0000-0002-0446-6129, Wolf, J. ORCID: https://orcid.org/0000-0003-3254-5868, Fan, D.N.Y. ORCID: https://orcid.org/0000-0001-6826-7076 and Schmitt, C.A. ORCID: https://orcid.org/0000-0002-4731-2226
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| 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. |
| Keywords: | B-Cell Lymphoma, CCAAT-Enhancer-Binding Protein-Beta, Cell Differentiation, Cell Lineage, Cell Plasticity, Cellular Senescence, Dendritic Cells, Diffuse Large B-Cell Lymphoma, Inbred C57BL Mice, Monocytes, Neoplastic Gene Expression Regulation, Proto-Oncogene Proteins, T-Lymphocytes, Trans-Activators, Transcription Factor AP-1, Transcription Factors, Tumor Cell Line, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 16 |
| Number: | 1 |
| Page Range: | 3079 |
| Date: | 31 March 2025 |
| Official Publication: | https://doi.org/10.1038/s41467-025-57429-x |
| PubMed: | View item in PubMed |
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