Abstract
Mature immunocompetent cells from the stem cell graft as well as early robust immune reconstitution are essential for the graft-vs. -tumor (GVT) effect to eliminate residual malignant cells after allogeneic hematopoietic stem cell transplantation (HSCT). In this prospective study we characterized graft composition of T- and NK cell subsets in 88 recipients of peripheral blood stem cell grafts with multicolor flowcytometry. Our primary aim was to analyze the impact of graft composition on immune reconstitution and clinical outcomes after transplantation. Patients transplanted with graft NK cell doses above the median value of 27 × 106/kg had significantly increased relapse-free-survival compared to patients transplanted with lower doses, HR 2.12 (95% CI 1.01–4.45, p = 0.04) Peripheral blood concentrations of NK cells obtained from donors before G-CSF mobilization were significantly correlated to graft NK cell doses (Spearman's ρ 0.53, p = 0.03). The dose of transplanted NK cells/kg correlated significantly with NK cell concentrations in patients early after transplantation (Spearman's ρ 0.26, p = 0.02, and ρ = 0.35, p = 0.001 for days 28 and 56, respectively). Early immune reconstitution above median values of NK cells was significantly associated with improved relapse-free survival (HR 2.84 [95% CI 1.29–6.28], p = 0.01, and HR 4.19 [95% CI 1.68–10.4], p = 0.002, for day 28 and 56, respectively). Early concentrations above the median value of the mature effector CD56dim NK cell subset were significantly associated with decreased relapse incidences at 1 year, 7% (95% CI 1.8–17) vs. 28% (95% CI 15–42), p = 0.04, and 7% (95% CI 1.8–18) vs. 26% (95% CI 14–40) %, p = 0.03, for days 28 and 56, respectively. The results suggest a protective effect of high doses of NK cells in grafts and during early immune reconstitution and support the perception of NK cells as innate effector cells with anti-tumor effects in the setting of allogeneic stem cell transplantation.
Highlights
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for various hematologic malignancies, it is still a procedure associated with a substantial risk of disease relapse and transplant-related morbidity and mortality (TRM) including graft-vs.-host disease (GVHD) [1,2,3]
In the TRM group, 4 patients died from aGVHD, three patients died from organ failure, three patients died from infection, two patients died from toxicity, one patient died from cGVHD, and one patient died from unknown causes other than relapse later than 2 years after transplantation
Our results show significant associations between high doses of graft natural killer (NK) cells and robust early NK cell immune reconstitution and increased relapse-free survival (RFS) after HSCT in patients transplanted with PBSC
Summary
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for various hematologic malignancies, it is still a procedure associated with a substantial risk of disease relapse and transplant-related morbidity and mortality (TRM) including graft-vs.-host disease (GVHD) [1,2,3]. MICA and MICB (MHC class 1 chain-related proteins A and B) and ULBPs (UL16-binding proteins) expressed by “stressed” cells (e.g., from infection, autoimmunity, malignant transformation) are able to engage the activating receptor NKG2D and trigger NK cell-mediated tumor elimination through perforin-meditated cytotoxicity, interleukin-priming (IL-12,15,18), and stimulation of costimulatory receptors [22, 23]. Though they are considered potent innate effector cells in the setting of HSCT [24,25,26], little is known about the NK cell graft composition and its possible impact on immune reconstitution after transplantation
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