Deep sequencing of bone marrow microenvironments of patients with del(5q) myelodysplastic syndrome reveals imprints of antigenic selection as well as generation of novel T-cell clusters as a response pattern to lenalidomide
| Autor: | Ulrich Germing, Daniel Nowak, Mascha Binder, Donjete Simnica, Wolf-Karsten Hofmann, Anne Marie Asemissen, Nuray Akyüz, Nicola Bonzanni, Thorben Mährle, Johann Christoph Jann, Pim Fuchs, Florian Nolte |
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| Rok vydání: | 2018 |
| Předmět: |
Male
T cell Clone (cell biology) Antineoplastic Agents Biology Article 03 medical and health sciences 0302 clinical medicine Immune system Antigens Neoplasm Bone Marrow T-Lymphocyte Subsets medicine Tumor Microenvironment Humans Lenalidomide Aged Myelodysplastic syndromes High-Throughput Nucleotide Sequencing Hematology Middle Aged medicine.disease Acquired immune system Prognosis medicine.anatomical_structure Case-Control Studies Myelodysplastic Syndromes Cancer research Immunoglobulin heavy chain Chromosomes Human Pair 5 Female Bone marrow Chromosome Deletion 030215 immunology medicine.drug Follow-Up Studies |
| Zdroj: | Haematologica |
| ISSN: | 1592-8721 |
| Popis: | In myelodysplastic syndromes with a partial deletion of the long arm of chromosome 5, del(5q), lenalidomide is believed to reverse anergic T-cell immunity in the bone marrow resulting in suppression of the del(5q) clone. In this study we used next-generation sequencing of immunoglobulin heavy chain (IGH) and T-cell receptor beta (TRB) rearrangements in bone marrow-residing and peripheral blood-circulating lymphocytes of patients with del(5q) myelodysplastic syndromes to assess the immune architecture and track adaptive immune responses during treatment with lenalidomide. The baseline bone marrow B-cell space in patients was comparable to that of age-matched healthy controls in terms of gene usage and IGH clonality, but showed a higher percentage of hypermutated IGH sequences, indicating an expanded number of antigen-experienced B lineage cells. Bone marrow B lineage clonality decreased significantly and hypermutated IGH clones normalized upon lenalidomide treatment, well in line with the proliferative effect on healthy antigen-inexperienced B-cell precursors previously described for this drug. The T-cell space in bone marrow of patients with del(5q) myelodysplastic syndromes showed higher TRB clonality compared to that of healthy controls. Upon lenalidomide treatment, myelodysplastic syndrome-specific T-cell clusters with low to medium spontaneous generation probabilities emerged; these clusters were shared across patients, indicating a common antigen-driven T-cell response pattern. Hence, we observed B lineage diversification and generation of new, antigen-dependent T-cell clusters, compatible with a model of adaptive immunity induced against the del(5q) clone by lenalidomide. Overall, this supports the concept that lenalidomide not only alters the functional T-cell state, but also the composition of the T- and B-cell repertoires in del(5q) myelodysplastic syndromes. |
| Databáze: | OpenAIRE |
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