Diego Gilioli, Simona Fusco, Teresa Tavella, Tatiana Volpari, Antonella Santoro, Martin Schönlein, Kety Giannetti, Edoardo Carsana, Nicolò Gualandi, Roberta Noberini, Chiara Brombin, Salvatore Russo, Sara Feola, Yvonne Giannoula, Rui M M Branca, Janne Lehtiö, Tiina M Sikanen, Markus Haapala, Laura Passerini, Angela Andrisani, Giacomo Farina, Alessia Zangari, Anastasia Conti, Lucrezia Della Volpe, Matteo Barcella, Stefano Beretta, Federico Mario Aletti, Matteo Giovanni Carrabba, Silvia Gregori, Chiara Bonini, Ivan Merelli, Fabio Ciceri, Vincenzo Cerullo, Tiziana Bonaldi, Luca Vago, Clemens A Schmitt, Raffaella Di Micco
Chemotherapy resistance and disease relapse are major determinants of treatment failure in acute myeloid leukemia (AML). Therapy-induced senescence (TIS) is one outcome of chemotherapy, but its immunological consequences in AML remain unclear. Here we show that ex vivo chemotherapy induces senescence in a subset of therapy-naïve AML samples. TIS is marked by elevated interferon signaling, upregulation of human leukocyte antigen (HLA) class I and II molecules, and increased presentation of leukemia- and senescence-associated peptides, conferring AML cells antigen-presenting cell-like features. These changes enhance autologous CD4+ and CD8+ T cell responses against AML, both ex vivo and in patient-derived xenograft models. TIS also restores AML sensitivity to immune checkpoint blockade therapy. Mechanistically, we identify reduced Polycomb Repressive Complex 2 (PRC2) activity as central to TIS induction and its immunogenicity. PRC2 inhibition reactivates senescence-related genes and HLA expression in non-senescent AML cells, enabling T cell activation. These findings uncover a senescence-driven immune mechanism with potential to improve therapy outcomes in AML.