title: T-cell number and subtype influence the disease course of primary chronic lymphocytic leukaemia xenografts in alymphoid mice.
abstract: Chronic lymphocytic leukaemia (CLL) cells require microenvironmental support for their proliferation. This can be recapitulated in highly immunocompromised hosts in the presence of T cells and other supporting cells. Current primary CLL xenograft models suffer from limited duration of tumour cell engraftment coupled with gradual T-cell outgrowth. Thus, a greater understanding of the interaction between CLL and T cells could improve their utility. In this study, using two distinct mouse xenograft models, we investigated whether xenografts recapitulate CLL biology, including natural environmental interactions with B-cell receptors and T cells, and whether manipulation of autologous T cells can expand the duration of CLL engraftment. We observed that primary CLL xenografts recapitulated both the tumour phenotype and T-cell repertoire observed in patients and that engraftment was significantly shorter for progressive tumours. A reduction in the number of patient T cells that were injected into the mice to 2-5% of the initial number or specific depletion of CD8(+) cells extended the limited xenograft duration of progressive cases to that characteristic of indolent disease. We conclude that manipulation of T cells can enhance current CLL xenograft models and thus expand their utility for investigation of tumour biology and pre-clinical drug assessment.
authors.affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Ceri E
authors.initials: CE
authors.lastname: Oldreive
authors.affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Skowronska
authors.affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Davies
authors.affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Parry
authors.affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Angelo
authors.initials: A
authors.lastname: Agathanggelou
authors.affiliation: CRUK Centre, Cancer Sciences Unit, University of Southampton, Southampton, SO16 6YD, UK.
authors.forename: Sergey
authors.initials: S
authors.lastname: Krysov
authors.affiliation: CRUK Centre, Cancer Sciences Unit, University of Southampton, Southampton, SO16 6YD, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.affiliation: Department of Pathology, Heart of England Hospital, Birmingham, B9 5SS, UK.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Rudzki
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Cronin
authors.affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Katerina
authors.initials: K
authors.lastname: Vrzalikova
authors.affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Murray
authors.affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Odintsova
authors.affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: A Malcolm R
authors.initials: AM
authors.lastname: Taylor
authors.affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Moss
authors.affiliation: School of Cancer Sciences, Department of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK stankovT@adf.bham.ac.uk.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D006085:Graft Survival; D064593:Heterografts; D006801:Humans; D016867:Immunocompromised Host; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010641:Phenotype; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D013997:Time Factors; D059016:Tumor Microenvironment
keywords: CLL; Mouse model; T-cell depletion