Abstract
T-cell receptor (TCR) γδ cells are perceived as innate-like effector cells with the possibility of mediating graft-vs. -tumor (GVT) without causing graft-vs.-host disease (GVHD) in the setting of hematopoietic allogeneic stem cell transplantation (HSCT). We conducted a prospective study to assess the clinical impact of TCR γδ cell immune reconstitution on overall survival, relapse-free-survival, relapse and GVHD. The impact of CD3, CD4, and CD8 T cells together with NK cells including subtypes were analyzed in parallel. A total of 108 patients with hematological malignancies transplanted with HLA-matched, T cell replete stem cell grafts were included for analyses of absolute concentrations of CD3, CD4, and CD8 positive T cells and NK cells together with a multi-color flow cytometry panel with staining for TCRαβ, TCRγδ, Vδ1, Vδ2, CD3, CD4, CD8, HLA-DR, CD196, CD45RO, CD45RA, CD16, CD56, CD337, and CD314 at 28, 56, 91, 180, and 365 days after transplantation. Immune reconstitution data including subsets and differentiation markers of T and NK cells during the first year after transplantation was provided. Patients with TCR γδ cell concentrations above the median value of 21 (0–416) × 106 cells/L 56 days after transplantation had significantly improved overall survival (p = 0.001) and relapse-free survival (p = 0.007) compared to patients with concentrations below this value. When day 56 cell subset concentrations were included as continuous variables, TCR γδ cells were the only T cell subsets with a significant impact on OS and RFS; the impact of TCR γδ cells remained statistically significant in multivariate analyses adjusted for pre-transplant risk factors. The risk of death from relapse was significantly decreased in patients with high concentrations of TCR γδ cells 56 days after transplantation (p = 0.003). Also, the risk of acute GVHD was significantly lower in patients with day 28 TCR γδ cell concentrations above the median of 18 × 106 cells/L compared to patients with low concentrations (p = 0.01). These results suggest a protective role of TCR γδ cells in relapse and GVHD and encourage further research in developing adaptive TCR γδ cell therapy for improving outcomes after HSCT.
Highlights
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients with hematological malignancies by elimination of recipient tumor cells by reactive immune cells from a donor [1]
Overall survival in all patients was 61%, relapsefree survival (RFS) was 47%, and transplant-related mortality (TRM) was 23% (95 CI 4.7–50%)
Two and four patients died from TRM prior to their day 28/56 samples
Summary
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients with hematological malignancies by elimination of recipient tumor cells by reactive immune cells from a donor [1]. The graft-vs.-leukemia (GVL) effect is originally thought to be mediated by conventional CD4 and CD8 positive T cells expressing the αβ T cell receptor (TCR) through alloreactivity caused by differences in human leukocyte antigens (HLA) and minor histocompatibility antigens (mHAg) between the recipient and the donor [2]. CD4/CD8 negative TCR γδ bearing T cells, which normally constitute about 1– 10% of the total T cell repertoire in peripheral blood, operate in an innate-like manner in the initiation phase of the immune reaction independently from HLA-antigen presentation [4]. In the setting of HSCT, the anti-leukemic properties together with the innatelike effector mechanisms in the absence of HLA-restriction suggest that TCR γδ cells mediate GVL in the absence of GVHD [9, 10]
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