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Senescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control

Author

Listed:
  • Dimitri Belenki

    (Campus Virchow Klinikum
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Paulina Richter-Pechanska

    (Campus Virchow Klinikum)

  • Zhiting Shao

    (Campus Virchow Klinikum)

  • Animesh Bhattacharya

    (Campus Virchow Klinikum)

  • Andrea Lau

    (Campus Virchow Klinikum)

  • José Américo Nabuco Leva Ferreira de Freitas

    (Faculté de Médecine de Créteil)

  • Gregor Kandler

    (Campus Virchow Klinikum)

  • Timon P. Hick

    (Campus Virchow Klinikum
    Humboldt-Universität zu Berlin)

  • Xiurong Cai

    (Campus Virchow Klinikum)

  • Eva Scharnagl

    (Medical Faculty)

  • Aitomi Bittner

    (Campus Virchow Klinikum)

  • Martin Schönlein

    (Campus Virchow Klinikum
    University Medical Center Hamburg-Eppendorf
    Vienna BioCenter (VBC))

  • Julia Kase

    (Campus Virchow Klinikum)

  • Katharina Pardon

    (Campus Virchow Klinikum)

  • Bernadette Brzezicha

    (Experimental Pharmacology & Oncology Berlin-Buch GmbH)

  • Nina Thiessen

    (Berlin Institute of Health)

  • Oliver Bischof

    (Faculté de Médecine de Créteil)

  • Jan R. Dörr

    (Campus Virchow Klinikum
    Charité-Universitätsmedizin Berlin
    Experimental and Clinical Research Center (ECRC) of the Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin)

  • Maurice Reimann

    (Campus Virchow Klinikum)

  • Maja Milanovic

    (Campus Virchow Klinikum
    Campus Benjamin Franklin
    partner site Berlin)

  • Jing Du

    (Medical Research Center and Department of Oncology Binzhou Medical University Hospital)

  • Yong Yu

    (Medical Faculty)

  • Björn Chapuy

    (Campus Benjamin Franklin)

  • Soyoung Lee

    (Campus Virchow Klinikum
    Medical Faculty)

  • Ulf Leser

    (Humboldt-Universität zu Berlin)

  • Claus Scheidereit

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association)

  • Jana Wolf

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association
    Free University Berlin)

  • Dorothy N. Y. Fan

    (Campus Virchow Klinikum
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association
    partner site Berlin)

  • Clemens A. Schmitt

    (Campus Virchow Klinikum
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association
    Medical Faculty
    partner site Berlin)

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.

Suggested Citation

  • Dimitri Belenki & Paulina Richter-Pechanska & Zhiting Shao & Animesh Bhattacharya & Andrea Lau & José Américo Nabuco Leva Ferreira de Freitas & Gregor Kandler & Timon P. Hick & Xiurong Cai & Eva Schar, 2025. "Senescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57429-x
    DOI: 10.1038/s41467-025-57429-x
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