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Relapse Post-Transplant Is Characterised By Persistently Elevated PD1 Expression on CD4 T Cells

Year: 2017

Type: article

Abstract: Relapse post allogeneic stem cell transplant(allo-SCT) remains a major cause of mortality. Impaired graft versus leukemia effects through T cell exhaustion or suppression may underpin relapse post-transplant. To understand the mechanism of relapse, we followed the evolution of T cell immunophenotypes with a particular focus on the exhaustion marker PD1 and regulatory T cells (Tregs) in subjects who relapsed and compared with non-relapsed subjects. Forty five subjects with hematological malignancies underwent HLA matched sibling allo-SCT at a single center between 2010 and 2015. All subjects received ex-vivo T cell depleted grafts with either CD3-CD19 cell depletion (n = 20) or CD34+ cell selection (n = 25) with the same conditioning regimen of cyclophosphamide, fludarabine, and total body irradiation with graft versus host disease(GVHD) prophylaxis of cyclosporine. At a median follow up of 498 days, 18 subjects (40%) had relapsed at a median of 245 days post allo-SCT. Peripheral blood mononuclear cells were collected from donors and recipients at 30 and 100 days post allo-SCT and at relapse in 8 subjects, to characterise Tregs and T cell exhaustion markers using multi-color flow cytometry. At day 30 post allo-SCT, PD1 expression was significantly elevated in the CD4 T cells of both relapsed and non-relapsed cohorts (%PD1+CD4+:79.7% ± 11.4 and 85.7% ± 10.2 respectively) as compared to donors (22.0 ± 8.9, P = .0078; P = .0001). PD1 expression was significantly decreased at day 100 in non-relapsed cohort (68.1% ± 17.6, P = .0001). In contrast, PD1 expression remained high in relapsing cohort on day 100 (73.3% ± 12.0) and at relapse (71.7% ± 13.1). Both naive Tregs (CD45RA+FOXP3dim) and CD25highFOXP3+ were increased on days 30 and 100 in the relapsed cohort when compared to the non-relapsed cohort. Relapse post allo-SCT was associated with a persisting exhaustion T cell phenotype and a greater preponderance of Tregs early after allo-SCT. Further studies are needed to evaluate the kinetics of T cell exhaustions for the development of a strategy to prevent relapse post-transplant.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2016.12.322