Introduction: Myelodysplastic syndromes (MDS) are haematopoietic neoplasms characterized by ineffective haemopoiesis and progression to acute myeloid leukemia in a relevant proportion of patients. Although an inflammatory component to MDS has long been recognized, only recently a more direct role of chronic innate immune signaling and inflammation in the pathogenesis of the disease has been issued. In this context, the involvement of dendritic cells (DCs) in MDS has been poorly characterized, so far. DCs are professional antigen-presenting cells crucial to the initiation and shaping of immune responses. The effects of DCs on immune responses depend partly on the activation state of DCs, and partly on the functional specialization of distinct subsets, with CD141+ conventional DCs (cDC1s) being critical in anti-cancer immune responses, mainly related to their ability to efficiently cross-present antigens, and activate cytotoxic T cells. In this study we characterized DC subsets in the peripheral blood of MDS patients. Methods: Whole blood samples obtained from 10 MDS patients and 16 healthy donors were stained with standard procedures and acquired on a FACSymphony (Becton Dickinson). The frequency of DC-lineage DCs, including cDC1s, cDC2 and plasmacytoid DCs (pDCs), and the frequency of inflammatory DCs, including monocyte-derived DCs (moDCs) and slanDCs, was analyzed in basal conditions. The phenotype of each DC subset was analyzed upon exposure of WB samples to proinflammatory and anti-inflammatory stimuli. Data were analyzed with FlowJo (FlowJo LLC). Results: All circulating DC subsets were significantly reduced in the blood of MDS patients compared with controls, this reduction not being correlated with disease severity. cDC1s from MDS patients showed an overall subversion of their inhibitory molecule repertoire, characterized by strong upregulation of ILT2 and downregulation of TIM-3 expression. We also observed an overall activation of cDC2s, and hyporesponsiveness of pDCs and cDC2s to TLR-mediated stimulation, likely reflecting the chronic hyperactivation of TLRs occurring in MDS and the subsequent desensitization of DCs to further TLR-induced stimulation. Conclusions: The observation that the immune checkpoint repertoire of cDC1s is subverted in MDS patients may pave the way for understanding the impact of these molecules on DC function. Further studies will be needed in order to investigate whether these cDC1 changes are also present in the bone marrow, whether they are sustained by the neoplastic process or they play a causative role in it, whether they are related to the immune dysregulation occurring in MDS, or whether they are shared with other types of cancer.

Immunophenotypic characterization of peripheral blood dendritic cell subsets in patients with myelodysplastic syndromes / S. Della Bella, C. Carenza, S. Franzese, F. Calcaterra, C. Di Vito, M. Ubezio, M. Della Porta, D. Mavilio. ((Intervento presentato al 19. convegno Euroconference on Clinical Cell Analysis tenutosi a Bergen, Norway nel 2019.

Immunophenotypic characterization of peripheral blood dendritic cell subsets in patients with myelodysplastic syndromes.

S. Della Bella
Primo
;
C. Carenza;S. Franzese;F. Calcaterra;C. Di Vito;M. Ubezio;D. Mavilio
2019

Abstract

Introduction: Myelodysplastic syndromes (MDS) are haematopoietic neoplasms characterized by ineffective haemopoiesis and progression to acute myeloid leukemia in a relevant proportion of patients. Although an inflammatory component to MDS has long been recognized, only recently a more direct role of chronic innate immune signaling and inflammation in the pathogenesis of the disease has been issued. In this context, the involvement of dendritic cells (DCs) in MDS has been poorly characterized, so far. DCs are professional antigen-presenting cells crucial to the initiation and shaping of immune responses. The effects of DCs on immune responses depend partly on the activation state of DCs, and partly on the functional specialization of distinct subsets, with CD141+ conventional DCs (cDC1s) being critical in anti-cancer immune responses, mainly related to their ability to efficiently cross-present antigens, and activate cytotoxic T cells. In this study we characterized DC subsets in the peripheral blood of MDS patients. Methods: Whole blood samples obtained from 10 MDS patients and 16 healthy donors were stained with standard procedures and acquired on a FACSymphony (Becton Dickinson). The frequency of DC-lineage DCs, including cDC1s, cDC2 and plasmacytoid DCs (pDCs), and the frequency of inflammatory DCs, including monocyte-derived DCs (moDCs) and slanDCs, was analyzed in basal conditions. The phenotype of each DC subset was analyzed upon exposure of WB samples to proinflammatory and anti-inflammatory stimuli. Data were analyzed with FlowJo (FlowJo LLC). Results: All circulating DC subsets were significantly reduced in the blood of MDS patients compared with controls, this reduction not being correlated with disease severity. cDC1s from MDS patients showed an overall subversion of their inhibitory molecule repertoire, characterized by strong upregulation of ILT2 and downregulation of TIM-3 expression. We also observed an overall activation of cDC2s, and hyporesponsiveness of pDCs and cDC2s to TLR-mediated stimulation, likely reflecting the chronic hyperactivation of TLRs occurring in MDS and the subsequent desensitization of DCs to further TLR-induced stimulation. Conclusions: The observation that the immune checkpoint repertoire of cDC1s is subverted in MDS patients may pave the way for understanding the impact of these molecules on DC function. Further studies will be needed in order to investigate whether these cDC1 changes are also present in the bone marrow, whether they are sustained by the neoplastic process or they play a causative role in it, whether they are related to the immune dysregulation occurring in MDS, or whether they are shared with other types of cancer.
Settore MED/04 - Patologia Generale
Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio
Settore MED/15 - Malattie del Sangue
Immunophenotypic characterization of peripheral blood dendritic cell subsets in patients with myelodysplastic syndromes / S. Della Bella, C. Carenza, S. Franzese, F. Calcaterra, C. Di Vito, M. Ubezio, M. Della Porta, D. Mavilio. ((Intervento presentato al 19. convegno Euroconference on Clinical Cell Analysis tenutosi a Bergen, Norway nel 2019.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/781483
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