title: Phenotype and immune function of lymph node and peripheral blood CLL cells are linked to transendothelial migration.
abstract: Several lines of evidence suggest that homing of tumor cells to lymphoid tissue contributes to disease progression in chronic lymphocytic leukemia (CLL). Here, we demonstrate that lymph node (LN)-derived CLL cells possess a distinct phenotype, and exhibit enhanced capacity for T-cell activation and superior immune synapse formation when compared with paired peripheral blood (PB) samples. LN-derived CLL cells manifest a proliferative, CXCR4(dim)CD5(bright) phenotype compared with those in the PB and higher expression of T-cell activation molecules including CD80, CD86, and HLA-D-related (DR). In addition, LN-CLL cells have higher expression of α4β1 (CD49d) which, as well as being a co-stimulatory molecule, is required for CLL cells to undergo transendothelial migration (TEM) and enter the proliferation centers of the LNs. Using an in vitro system that models circulation and TEM, we showed that the small population of CLL cells that migrate are CXCR4(dim)CD5(bright) with higher CD49d, CD80, CD86, and HLA-DR compared with those that remain circulating; a phenotype strikingly similar to LN-derived CLL cells. Furthermore, sorted CD49d(hi) CLL cells showed an enhanced capacity to activate T cells compared with CD49d(lo) subpopulations from the same patient. Thus, although PB-CLL cells have a reduced capacity to form immune synapses and activate CD4(+) T cells, this was not the case for LN-CLL cells or those with the propensity to undergo TEM. Taken together, our study suggests that CLL cell immunologic function is not only modulated by microenvironmental interactions but is also a feature of a subpopulation of PB-CLL cells that are primed for lymphoid tissue homing and interaction with T cells.
authors.affiliation: Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom;
authors.forename: Marta
authors.initials: M
authors.lastname: Pasikowska
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom; and.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Walsby
authors.affiliation: Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom;
authors.forename: Benedetta
authors.initials: B
authors.lastname: Apollonio
authors.affiliation: Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom;
authors.forename: Kirsty
authors.initials: K
authors.lastname: Cuthill
authors.affiliation: Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Phillips
authors.affiliation: Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom;
authors.forename: Eve
authors.initials: E
authors.lastname: Coulter
authors.affiliation: King's College London, Institute of Liver Sciences, London, United Kingdom.
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Longhi
authors.affiliation: King's College London, Institute of Liver Sciences, London, United Kingdom.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom;
authors.forename: Deborah
authors.initials: D
authors.lastname: Yallop
authors.affiliation: Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom;
authors.forename: Linda D
authors.initials: LD
authors.lastname: Barber
authors.affiliation: Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom;
authors.forename: Piers
authors.initials: P
authors.lastname: Patten
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom; and.
authors.forename: Chris
authors.initials: C
authors.lastname: Fegan
authors.affiliation: Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom;
authors.forename: Alan G
authors.initials: AG
authors.lastname: Ramsay
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom; and.
authors.forename: Chris
authors.identifier: 0000-0003-3603-8839
authors.initials: C
authors.lastname: Pepper
authors.affiliation: Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom;
authors.forename: Stephen
authors.initials: S
authors.lastname: Devereux
authors.affiliation: Department of Haemato-Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom;
authors.forename: Andrea G S
authors.identifier: 0000-0001-9795-1280
authors.initials: AG
authors.lastname: Buggins
mesh_terms: D015703:Antigens, CD / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D004730:Endothelium, Vascular / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000276:immunology*; D057705:Transendothelial and Transepithelial Migration / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D009363:Neoplasm Proteins