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Deep sequencing and flow cytometric characterization of expanded effector memory CD8+CD57+ T cells frequently reveals T-cell receptor Vβ oligoclonality and CDR3 homology in acquired aplastic anemia

ABSTRACT: In this work, we investigated the frequency and oligoclonal expansion of effector CD28-CD57+ memory cells in CD8+ T cell compartments and the T-cell Receptor (TCR) Vβ repertoire in acquired aplastic anemia (AA) to provide additional evidence to the immune hypothesis in AA pathophysiology. Using flow cytometry, deep sequencing, and computational methods, we examined the blood of 32 AA patients and 29 appropriate controls for Vβ usage; eight of these patients showing CD8+CD57+ expansion and three healthy subjects were subjected to TCR deep sequencing to confirm the clonality. We showed that CD8+CD57+ cells were frequently expanded with oligoclonal characteristics in AA, and patients and healthy donors shared CD8+ clonotypes by complementarity-determining region 3 sequences analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE101660 | GEO | 2018/05/05

REPOSITORIES: GEO

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Project description:Background and methods: CD19-directed CAR T-cell therapy (CAR-T) has emerged as a promising treatment modality for multiple B-cell malignancies. However, its utility is hampered by a unique toxicity profile that classically includes cytokine release syndrome (CRS) and neurotoxicity. Hematological toxicity represents a vexing and common side effect. Cytopenia can occur long after lymphodepleting chemotherapy and resolution of CRS and is often prolonged and biphasic in nature. Some patients have been described to develop severe bone marrow (BM) failure, which can predispose for severe infections and high non-relapse mortality. Overall, the underlying pathomechanisms of CAR-T-related hematotoxicity remain poorly understood. We performed flow cytometry, serum cytokine profiling, single cell transcriptome and TCR-sequencing of PBMCs from pre-/post-treatment sampels of a patient with DLBCL-type Richter Transformation receiving tisagenlecleucel in a standard-of-care setting and present one marrow failure. Results: The advent of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of refractory B-cell malignancies. Real-world evidence has highlighted the high incidence of hematological toxicity, including prolonged and profound cytopenia. Here, we present the case of bone marrow failure in a 57-year old man with DLBCL-type Richter Transformation receiving tisagenlecleucel in a standard-of-care setting. The clinical course was notable for underlying bone marrow infiltration, severe cytokine release syndrome and multiple infectious complications in the setting of prolonged, profound neutropenia. Cytokine profiling revealed a signature consistent with acquired aplastic anemia – including downregulation of CD40-L and EGF. Flow cytometric analyses demonstrated expansion of both CAR and non-CAR bearing CD8+ CD57+ T-cells in the bone marrow, an immunophenotype linked to oligoclonality in aplastic anemia. On a single-cell level, this was accompanied by T-cell receptor Vβ oligoclonal expansion and post-CAR clonal drift. Gene expression profiling revealed upregulation of exhaustion markers on (CAR) T-cells and decreased expression of genes involved in STAT signalling and inflammatory response. Conclusion: In conclusion, this case highlights the complex nature of CAR-T-related hematological toxicity and introduces oligoclonal (CAR) T-cell expansion as a potential contributing pathomechanism.

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Deep sequencing and flow cytometric characterization of expanded effector memory CD8+CD57+ T cells frequently reveals T-cell receptor Vβ oligoclonality and CDR3 homology in acquired aplastic anemia

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