Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation
Abstract Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experiences...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38113-4 |
| _version_ | 1797811419724382208 |
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| author | Simona Pagliuca Carmelo Gurnari Colin Hercus Sébastien Hergalant Sanghee Hong Adele Dhuyser Maud D’Aveni Alice Aarnink Marie Thérèse Rubio Pierre Feugier Francesca Ferraro Hetty E. Carraway Ronald Sobecks Betty K. Hamilton Navneet S. Majhail Valeria Visconte Jaroslaw P. Maciejewski |
| author_facet | Simona Pagliuca Carmelo Gurnari Colin Hercus Sébastien Hergalant Sanghee Hong Adele Dhuyser Maud D’Aveni Alice Aarnink Marie Thérèse Rubio Pierre Feugier Francesca Ferraro Hetty E. Carraway Ronald Sobecks Betty K. Hamilton Navneet S. Majhail Valeria Visconte Jaroslaw P. Maciejewski |
| author_sort | Simona Pagliuca |
| collection | DOAJ |
| description | Abstract Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experiences relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse. |
| first_indexed | 2024-03-13T07:22:25Z |
| format | Article |
| id | doaj.art-8c1bcd077dcf4d8795e32c0ba12bd5cc |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T07:22:25Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-8c1bcd077dcf4d8795e32c0ba12bd5cc2023-06-04T11:33:41ZengNature PortfolioNature Communications2041-17232023-05-0114111210.1038/s41467-023-38113-4Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantationSimona Pagliuca0Carmelo Gurnari1Colin Hercus2Sébastien Hergalant3Sanghee Hong4Adele Dhuyser5Maud D’Aveni6Alice Aarnink7Marie Thérèse Rubio8Pierre Feugier9Francesca Ferraro10Hetty E. Carraway11Ronald Sobecks12Betty K. Hamilton13Navneet S. Majhail14Valeria Visconte15Jaroslaw P. Maciejewski16Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland ClinicDepartment of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland ClinicNovocraft Technologies Sdn BhdInserm UMR-S 1256 Nutrition-Genetics-Environmental Risk Exposure, University of LorraineDivision of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of MedicineCNRS UMR 7365, IMoPA, Biopole of University of LorraineDepartment of Hematology, CHRU de NancyCNRS UMR 7365, IMoPA, Biopole of University of LorraineDepartment of Hematology, CHRU de NancyDepartment of Hematology, CHRU de NancyDivision of Oncology, Department of Medicine, Washington University School of Medicine in St. LouisLeukemia Program, Hematology Department, Taussig Cancer Institute, Cleveland ClinicBlood and Marrow Transplant Program, Taussig Cancer Institute, Cleveland ClinicBlood and Marrow Transplant Program, Taussig Cancer Institute, Cleveland ClinicSarah Cannon Transplant and Cellular Therapy NetworkDepartment of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland ClinicDepartment of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland ClinicAbstract Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experiences relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.https://doi.org/10.1038/s41467-023-38113-4 |
| spellingShingle | Simona Pagliuca Carmelo Gurnari Colin Hercus Sébastien Hergalant Sanghee Hong Adele Dhuyser Maud D’Aveni Alice Aarnink Marie Thérèse Rubio Pierre Feugier Francesca Ferraro Hetty E. Carraway Ronald Sobecks Betty K. Hamilton Navneet S. Majhail Valeria Visconte Jaroslaw P. Maciejewski Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation Nature Communications |
| title | Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation |
| title_full | Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation |
| title_fullStr | Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation |
| title_full_unstemmed | Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation |
| title_short | Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation |
| title_sort | leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation |
| url | https://doi.org/10.1038/s41467-023-38113-4 |
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