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

Cellular senescence is a stress-inducible state switch particularly relevant in aging, tumorigenesis and cancer therapy. Beyond a lasting arrest, cells are characterized by profound chromatin remodeling and transcriptional reprogramming. Applying bulk and single-cell analyses, we report here myeloid-skewed aberrant lineage plasticity and its immunological ramifications in therapy-induced senescence (TIS) of primary B-cell lymphoma of human and murine origin. We found myeloid transcription factor networks, specifically AP-1-, C/EBPb- and PU.1-governed transcriptional programs enriched in TIS but not in equally chemotherapy-exposed senescence-incapable lymphoma cells. Dependent on these master transcription factors, TIS lymphoma cells adopted markers and properties reminiscent of monocytic-dendritic cell (DC) differentiation. Importantly, neoplastic Eu-myc B-cells with TIS-associated DC plasticity exhibited significantly longer tumor-free survival upon chemotherapy in immune-competent recipient mice in vivo, and were preferentially lysed by T-cells in vitro. Consistently, superior long-term outcome was also seen in DLBCL patients with high-level lymphoma 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.