Both T cell and natural killer (NK) cell reconstitution have been shown to affect clinical outcomes after hematopoietic stem cell transplantation (HSCT). Killer immunoglobulin-like receptor (KIR) interactions between alloreactive NK cells and their targets can prevent relapse, but may be dysregulated, especially after T cell replete HSCT. T cell recovery is also affected by the stem cell source and T cell content of the graft. To better understand the effects of various NK and T cell subsets we evaluated lymphocyte recovery in 304 adult patients who received either UCB (n=116), Sib (n=84) or Auto (n=94) HSCT for hematologic malignancies between 2003 and 2010 at the University of Minnesota. Peripheral blood mononuclear cells obtained at 3 months after HSCT were stained with CD56, CD3, CD4, CD8, and a cocktail of anti-NK cell KIR antibodies to determine the relative percentage of lymphocyte subsets by flow cytometry. The absolute lymphocyte count (ALC) was measured and used to calculate the absolute (Abs) number of T and NK cells and their subsets. ALC recovery at 3 months was similar among groups (UCB: 901.9 ± 74.5, Sib 890.2 ± 73.0 and Auto 1076.7± 69.4 cells/ul). Abs NK cells were highest in the UCB cohort (375.4 ± 24.9) vs. Sib (183.8 ± 15.4; p<0.0001) or Auto (160.7 ± 11.0; p<0.0001), as were the CD56bright and KIR+ subsets (data not shown). In contrast, Abs T cell recovery was lowest in the UCB group (300.8 ± 39.6) vs. Sib (578.5 ± 57.9; p<0.0001) or Auto (737.3 ± 60.4; p<0.0001). Accordingly, the lowest Abs CD4 count was in the UCB group (158.8 ± 14.7) vs. Sib (272.5 ± 23.5; p<0.0001) or Auto (223.6 ± 20.2; p=0.01), with a similar pattern observed for Abs CD8 counts. We then examined the effect of lymphocyte recovery on clinical outcomes. Multivariate models were constructed for each transplant group with relevant covariates (risk status, conditioning, sex, age, number of UCB units, CMV status, HLA matching (4/6, 5/6, or 6/6), and ABO matching). The most significant effect of lymphocyte recovery on outcomes was observed specifically in the UCB group, where higher ALC was associated with improved OS with a hazard ratio (HR) of 0.86 (95% CI 0.78–0.95) for each unit increase in ALC of 100 cells/ul (p <0.01). A similar trend was observed in Sib recipients but not in the Auto group. Specifically, increases in Abs T cells (HR 0.75 [95% CI 0.58–0.98]; p=0.034), Abs CD4 count (HR 0.63 [95% CI 0.42–0.95]; p=0.03), Abs CD8 count (HR 0.31 [95% CI 0.13–0.73]; p=0.01) and to a lesser extent Abs NK cells (HR 0.85 [95% CI 0.71–1.02]; p=0.085) were associated with improved OS. In the Sib cohort, higher Abs CD4 count was associated with improved OS (HR 0.43 [95% CI 0.20–0.92]; p=0.03) and decreased relapse (HR 0.37 [95% CI 0.37–1.00]; p=0.02), with no other factor having a significant impact. In the Auto group, only Abs NK (HR 0.40 [95% CI 0.16–0.99]; p=0.05) and to a lesser extent Abs KIR+ NK cells (HR 0.17 [95% CI 0.02–1.36]; p=0.09) were associated with improved OS but no other outcomes. The effect of Abs CD4 count on OS in all groups is shown in Figure 1 with survival stratified by quartiles.
In summary, rapid recovery of T cells predicts significantly better survival in patients undergoing UCB and Sib HSCT, while the NK cell effects are less pronounced. In contrast, NK cell effects predominate after Auto HCT. This suggests that more rapid T cell recovery is critical for survival and that defects in NK cell education after allogeneic HSCT may affect their function such that just increasing numbers may not be sufficient for clinical benefit. Appropriate modifications to immune suppression or the use of agents that promote T cell (IL-7) and/or NK cell (IL-15) function and survival may positively influence survival outcomes.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.