Senescence-associated lineage-aberrant plasticity evokes T-cell-mediated tumor control
Dimitri Belenki, Paulina Richter‐Pechańska, Zhiting Shao, Animesh Bhattacharya, Andrea Lau, José Américo Nabuco Leva Ferreira de Freitas, Gregor Kandler, Timon 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, Bjoern Chapuy, Soyoung Lee, Ulf Leser, Claus Scheidereit, Jana Wolf, Dorothy Ngo-Yin Fan, Clemens A. Schmitt
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.