Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes

Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Bijender Kumar, Natthakan Thongon, Feiyang Ma, Kelly S. Chien, Yi J. Kim, Hui Yang, Sanam Loghavi, Roselyn Tan, Vera Adema, Zongrui Li, Tomoyuki Tanaka, Hidetaka Uryu, Rashmi Kanagal-Shamanna, Gheath Al-Atrash, Rafael Bejar, Pinaki Prosad Banerjee, Sophia Lynn Cha, Guillermo Montalban-Bravo, Max Dougherty, Maria Claudina Fernandez Laurita, Noelle Wheeler, Baosen Jia, Eirini P. Papapetrou, Franco Izzo, Daniela E. Dueñas, Salome McAllen, Yiqian Gu, Gabriele Todisco, Francesca Ficara, Matteo Giovanni Porta, Abhinav Jain, Koichi Takahashi, Karen Clise-Dwyer, Stephanie Halene, Maria Teresa Sabrina Bertilaccio, Guillermo Garcia-Manero, May Daher () and Simona Colla ()
Additional contact information
Juan Jose Rodriguez-Sevilla: The University of MD Anderson Cancer Center
Irene Ganan-Gomez: The University of MD Anderson Cancer Center
Bijender Kumar: The University of Texas MD Anderson Cancer Center
Natthakan Thongon: The University of MD Anderson Cancer Center
Feiyang Ma: Northwestern University
Kelly S. Chien: The University of MD Anderson Cancer Center
Yi J. Kim: The University of MD Anderson Cancer Center
Hui Yang: The University of MD Anderson Cancer Center
Sanam Loghavi: The University of Texas MD Anderson Cancer Center
Roselyn Tan: Moores Cancer Center
Vera Adema: The University of MD Anderson Cancer Center
Zongrui Li: The University of MD Anderson Cancer Center
Tomoyuki Tanaka: The University of MD Anderson Cancer Center
Hidetaka Uryu: The University of MD Anderson Cancer Center
Rashmi Kanagal-Shamanna: The University of Texas MD Anderson Cancer Center
Gheath Al-Atrash: The University of Texas MD Anderson Cancer Center
Rafael Bejar: Moores Cancer Center
Pinaki Prosad Banerjee: The University of Texas MD Anderson Cancer Center
Sophia Lynn Cha: The University of Texas MD Anderson Cancer Center
Guillermo Montalban-Bravo: The University of MD Anderson Cancer Center
Max Dougherty: Icahn School of Medicine at Mount Sinai
Maria Claudina Fernandez Laurita: Icahn School of Medicine at Mount Sinai
Noelle Wheeler: Icahn School of Medicine at Mount Sinai
Baosen Jia: Icahn School of Medicine at Mount Sinai
Eirini P. Papapetrou: Icahn School of Medicine at Mount Sinai
Franco Izzo: Icahn School of Medicine at Mount Sinai
Daniela E. Dueñas: The University of Texas MD Anderson Cancer Center
Salome McAllen: The University of Texas MD Anderson Cancer Center
Yiqian Gu: University of California Los Angeles
Gabriele Todisco: Humanitas University
Francesca Ficara: IRCCS Humanitas Research Hospital
Matteo Giovanni Porta: Humanitas University
Abhinav Jain: The University of MD Anderson Cancer Center
Koichi Takahashi: The University of MD Anderson Cancer Center
Karen Clise-Dwyer: The University of Texas MD Anderson Cancer Center
Stephanie Halene: Yale University School of Medicine
Maria Teresa Sabrina Bertilaccio: The University of MD Anderson Cancer Center
Guillermo Garcia-Manero: The University of MD Anderson Cancer Center
May Daher: The University of Texas MD Anderson Cancer Center
Simona Colla: The University of MD Anderson Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58662-0

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