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Expression of Intratumoral Forkhead Box Protein 3 in Posttransplant Lymphoproliferative Disorders: Clinical Features and Survival Outcomes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Halmstad Hospital.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
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2015 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 99, no 5, 1036-1042 p.Article in journal (Refereed) Published
Abstract [en]

Background. The infiltration of regulatory T cells (Tregs) in lymphomas is associated with better prognosis for some types of lymphomas, but knowledge of their role in posttransplant lymphoproliferative disorders (PTLDs) is limited. We therefore investigated the association between the expression of the Treg marker forkhead box protein 3 (FoxP3) in biopsies of PTLDs and survival, PTLD subtype, and clinical characteristics.

Methods. Seventy-four cases of PTLD after solid organ transplantation with sufficient material for further analysis were included from a population-based study of PTLDs in Sweden. The PTLD biopsies were reevaluated and stained with the 236A/E7 antibody to detect FoxP3 in lymphoma tissue. Detailed clinical data were collected retrospectively from medical records.

Results. Based on a cutoff level of 29 FoxP3+ cells per mm2, most (80%) of the PTLDs were FoxP3-. Forty-seven of 74 PTLDs displayed no FoxP3+ cells at all. The frequency of FoxP3+ cells did not influence median overall survival. The FoxP3- PTLDs were more frequently of T-cell phenotype (P=0.04), located at the graft (P=0.03), occurred earlier after transplantation (P=0.04), were more likely to develop in lung recipients (P=0.04), and in patients that had received anti T-cell globulin as induction therapy (P=0.02). The FoxP3+ PTLDs were associated with hepatitis C seropositivity (P=0.03). In multivariate analysis, B-cell PTLD and hepatitis C infection were independent predictors of FoxP3 positivity.

Conclusion. Our findings suggest that intratumoral FoxP3+ Tregs do not influence survival in patients with PTLD. FoxP3+ Tregs are rare in PTLD, possibly because of heavy immunosuppression.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2015. Vol. 99, no 5, 1036-1042 p.
Keyword [en]
Regulatory T cell, FoxP3, Posttransplant lymphoproliferative disorders, lymphoma, microenvironment, survival, clinical features, hepatitis C, Treg, immunosuppression, antithymocyte globulin
National Category
Cancer and Oncology
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-234073DOI: 10.1097/TP.0000000000000415ISI: 000353962700030PubMedID: 25211518OAI: oai:DiVA.org:uu-234073DiVA: diva2:755432
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2014-10-14 Created: 2014-10-14 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Posttransplant Lymphoproliferative Disorders: Studies of Epstein-Barr Virus, Regulatory T Cells and Tumor Origin
Open this publication in new window or tab >>Posttransplant Lymphoproliferative Disorders: Studies of Epstein-Barr Virus, Regulatory T Cells and Tumor Origin
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Epstein-Barr virus (EBV) infects almost all humans and establishes lifelong latency in B cells. Posttransplant lymphoproliferative disorder (PTLD) is a rare but serious complication after transplantation triggered by immunosuppression and often related to EBV infection. The aim of this thesis was to study the role of EBV in relation to clinical and histological features of PTLD, regulatory T cells (Tregs), and donor or recipient origin of PTLD.

EBV surveillance after allogeneic hematopoietic stem cell transplantation (allo-HSCT) showed that EBV reactivations were common, but that symptomatic EBV disease (including PTLD) only occurred in the high-risk group (unrelated or mismatched related grafts, reduced-intensity conditioning). A threshold of 1000 copies/ml plasma distinguished EBV disease from asymptomatic reactivations.

In a population-based cohort of 135 PTLDs/lymphomas after solid organ transplantation (SOT) almost half were EBV. EBV+ PTLDs were associated with B cell phenotype, non-germinal center subtype of diffuse large B cell lymphoma (DLBCL), early-onset, graft involvement, antithymocyte globulin treatment, and younger age. EBV PTLDs were associated with T cell phenotype, bone marrow involvement, and hepatitis C. Most PTLDs displayed few or no intratumoral Tregs with the marker FoxP3, possibly due to heavy immuno­suppres­sion. Half of both FoxP3+ and FoxP3PTLDs were EBV+. FoxP3+ PTLDs were associated with B cell phenotype and hepatitis C. All PTLDs for which tumor origin could be determined were recipient-derived and half of them were EBV+. Eight of twelve recipient-derived graft PTLDs were disseminated outside the graft. T cell PTLD and hepatitis C were independently associated with inferior overall survival, whereas subtype of DLBCL, FoxP3-expression, and EBV-status did not influence survival.

In conclusion, monitoring of EBV DNAemia in high-risk patients after allo-HSCT and pre-emptive therapy is valuable for prevention of PTLD. Use of anti­thymocyte globulin increases the risk for EBV+ PTLDs after allo-HSCT and SOT. With long follow-up time, a large proportion of PLTDs after SOT are EBVwith a different clinical presentation. Tregs are rare in PTLD and do not affect survival. The vast majority of PTLDs after SOT is of recipient origin. Graft PTLDs are more likely recipient-derived if disseminated. EBV-status is not associated with intratumoral Tregs or PTLD of recipient origin.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 107 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1043
Keyword
PTLD, Lymphoma, Epstein-Barr Virus, EBV DNAemia, FoxP3, Treg, Microenvironment, Cell of Origin, Recipient, Transplantation, Immunosuppression, Hepatitis C, Survival
National Category
Cancer and Oncology Infectious Medicine
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-234130 (URN)978-91-554-9074-4 (ISBN)
Public defence
2014-11-29, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-11-05 Created: 2014-10-14 Last updated: 2015-02-03

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Berglund, DavidKinch, AmelieBacklin, CarinEnblad, GunillaLarsson, ErikMolin, DanielPauksens, KarlisBaecklund, Eva

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