Scientific publications
Natural killer cells' functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes
Juan Jose Rodriguez-Sevilla # 1, Irene Ganan-Gomez # 1, Bijender Kumar # 2, Natthakan Thongon 1, Feiyang Ma 3, Kelly S Chien 1, Yi J Kim 4, Hui Yang 1, Sanam Loghavi 5, Roselyn Tan 6, Vera Adema 1, Zongrui Li 4, Tomoyuki Tanaka 4, Hidetaka Uryu 4, Rashmi Kanagal-Shamanna 5, Gheath Al-Atrash 2, Rafael Bejar 6, Pinaki Prosad Banerjee 2, Sophia Lynn Cha 2, Guillermo Montalban-Bravo 1, Max Dougherty 7 8, Maria Claudina Fernandez Laurita 7 8, Noelle Wheeler 7 8, Baosen Jia 7 8, Eirini P Papapetrou 7 8, Franco Izzo 7 8, Daniela E Dueñas 9, Salome McAllen 9, Yiqian Gu 10, Gabriele Todisco 11 12, Francesca Ficara 12 13, Matteo Giovanni Della Porta 11 12, Abhinav Jain 14, Koichi Takahashi 1 4, Karen Clise-Dwyer 2, Stephanie Halene 15, Maria Teresa Sabrina Bertilaccio 1, Guillermo Garcia-Manero 1, May Daher 16, Simona Colla 17
Abstract
Dissecting the preneoplastic disease states' biological mechanisms that precede tumorigenesis can lead to interventions that can slow down disease progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail to eradicate aberrant hematopoietic stem cells (HSCs), most of which are mutated by the time of diagnosis. Here, we sought to elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias of undetermined significance (CCUS), the pre-malignant stage of MDS. We used multi-omic single-cell approaches and functional in vitro studies to show that immune escape at disease initiation is mainly mediated by mutant, dysfunctional natural killer (NK) cells with impaired cytotoxic capability against cancer cells. Preclinical in vivo studies demonstrated that injecting NK cells from healthy donors efficiently depleted CCUS mutant cells while allowing normal cells to regenerate hematopoiesis. Our findings suggest that early intervention with adoptive cell therapy can prevent or delay the development of MDS.
CITA DEL ARTÍCULO Nat Commun. 2025 Apr 11;16(1):3450. doi: 10.1038/s41467-025-58662-0.
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