Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes
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 pharmacologica...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58662-0 |
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| author | 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 Della Porta Abhinav Jain Koichi Takahashi Karen Clise-Dwyer Stephanie Halene Maria Teresa Sabrina Bertilaccio Guillermo Garcia-Manero May Daher Simona Colla |
| author_facet | 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 Della Porta Abhinav Jain Koichi Takahashi Karen Clise-Dwyer Stephanie Halene Maria Teresa Sabrina Bertilaccio Guillermo Garcia-Manero May Daher Simona Colla |
| author_sort | Juan Jose Rodriguez-Sevilla |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-85cf5d13969f40a59636bfe52c4b3b60 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-85cf5d13969f40a59636bfe52c4b3b602025-08-20T03:06:52ZengNature PortfolioNature Communications2041-17232025-04-0116111410.1038/s41467-025-58662-0Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromesJuan Jose Rodriguez-Sevilla0Irene Ganan-Gomez1Bijender Kumar2Natthakan Thongon3Feiyang Ma4Kelly S. Chien5Yi J. Kim6Hui Yang7Sanam Loghavi8Roselyn Tan9Vera Adema10Zongrui Li11Tomoyuki Tanaka12Hidetaka Uryu13Rashmi Kanagal-Shamanna14Gheath Al-Atrash15Rafael Bejar16Pinaki Prosad Banerjee17Sophia Lynn Cha18Guillermo Montalban-Bravo19Max Dougherty20Maria Claudina Fernandez Laurita21Noelle Wheeler22Baosen Jia23Eirini P. Papapetrou24Franco Izzo25Daniela E. Dueñas26Salome McAllen27Yiqian Gu28Gabriele Todisco29Francesca Ficara30Matteo Giovanni Della Porta31Abhinav Jain32Koichi Takahashi33Karen Clise-Dwyer34Stephanie Halene35Maria Teresa Sabrina Bertilaccio36Guillermo Garcia-Manero37May Daher38Simona Colla39Department of Leukemia, The University of MD Anderson Cancer CenterDepartment of Leukemia, The University of MD Anderson Cancer CenterDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of MD Anderson Cancer CenterDepartment of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern UniversityDepartment of Leukemia, The University of MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of MD Anderson Cancer CenterDepartment of Leukemia, The University of MD Anderson Cancer CenterDepartment of Hematopathology, The University of Texas MD Anderson Cancer CenterMoores Cancer Center, University of California San Diego, Moores Cancer CenterDepartment of Leukemia, The University of MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of MD Anderson Cancer CenterDepartment of Hematopathology, The University of Texas MD Anderson Cancer CenterDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer CenterMoores Cancer Center, University of California San Diego, Moores Cancer CenterDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer CenterDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of MD Anderson Cancer CenterDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer CenterDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer CenterBioinformatics Interdepartmental Program, University of California Los AngelesDepartment of Biomedical Sciences, Humanitas UniversityIRCCS Humanitas Research HospitalDepartment of Biomedical Sciences, Humanitas UniversityDepartment of Epigenetics and Molecular Carcinogenesis, Center for Cancer Epigenetics, The University of MD Anderson Cancer CenterDepartment of Leukemia, The University of MD Anderson Cancer CenterDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer CenterSection of Hematology, Department of Internal Medicine and Yale Cancer Center, Yale University School of MedicineDepartment of Leukemia, The University of MD Anderson Cancer CenterDepartment of Leukemia, The University of MD Anderson Cancer CenterDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer CenterDepartment of Leukemia, The University of MD Anderson Cancer CenterAbstract 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.https://doi.org/10.1038/s41467-025-58662-0 |
| spellingShingle | 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 Della Porta Abhinav Jain Koichi Takahashi Karen Clise-Dwyer Stephanie Halene Maria Teresa Sabrina Bertilaccio Guillermo Garcia-Manero May Daher Simona Colla Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes Nature Communications |
| title | Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes |
| title_full | Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes |
| title_fullStr | Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes |
| title_full_unstemmed | Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes |
| title_short | Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes |
| title_sort | natural killer cells functional impairment drives the immune escape of pre malignant clones in early stage myelodysplastic syndromes |
| url | https://doi.org/10.1038/s41467-025-58662-0 |
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