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<p>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-<i>myc</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月31日

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  • 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 Scharnagl,
  • Aitomi Bittner,
  • Martin Schönlein,
  • Julia Kase,
  • Katharina Pardon,
  • Bernadette Brzezicha,
  • Nina Thiessen,
  • Oliver Bischof,
  • Jan R. Dörr,
  • Maurice Reimann,
  • Maja Milanovic,
  • Jing Du,
  • Yong Yu,
  • Björn Chapuy,
  • Soyoung Lee,
  • Ulf Leser,
  • Claus Scheidereit,
  • Jana Wolf,
  • Dorothy N. Y. Fan,
  • Clemens A. Schmitt

摘要

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.